bluuebunny/crossref_metadata_2025 huggingface dataset:
Hearing impairment in Parkinson's disease: Expanding the nonmotor phenotype
Authors: Vitale Carmine , Marcelli Vincenzo , Allocca Roberto , Santangelo Gabriella , Riccardi Pasquale , Erro Roberto , Amboni Marianna , Pellecchia Maria Teresa , Cozzolino Autilia , Longo Katia , Picillo Marina , Moccia Marcello , Agosti Valeria , Sorrentino G. , Cavaliere Michele , Marciano Elio , Barone Paolo
Published: October 2012

The objective of this study was to evaluate hearing impairment in patients affected by Parkinson's disease compared with hearing scores observed in normal age‐ and sex‐matched controls. One hundred eighteen consecutive patients with a clinical diagnosis of Parkinson's disease were screened. Severity of motor symptoms and staging were measured with the Unified Parkinson's Disease Rating Scale (section III) and the Hoehn and Yahr scale. Audiometric evaluation consisted of a comprehensive audiologic case history and questionnaire, visual otoscopic examination, acoustic immittance measures (tympanogram and acoustic reflexes), pure tone audiometry, and measurement of brain stem auditory‐evoked potentials. Healthy age‐ and sex‐matched subjects were selected as the control group. One hundred six of 118 patients were enrolled. Pure tone audiometry revealed age‐dependent high‐frequency hearing loss in patients with Parkinson's disease compared with both normative values and values for healthy age‐ and sex‐matched controls (75/106 [71%], χ2 = 5.959, P = .02; 92/106 [86.8%] vs 60/106 [56.6%], χ2 = 23.804, P < .001, respectively). Pure tone audiometry scores correlated with Hoehn and Yahr scale scores (P < .05). Brain stem auditory‐evoked potentials were normal in all patients. Our patients with Parkinson's disease showed age‐dependent peripheral, unilateral, or bilateral hearing impairment. Whether these auditory deficits are intrinsic to Parkinson's disease or secondary to a more complex impaired processing of sensorial inputs occurring over the course of illness remains to be determined. Because α‐synuclein is located predominately in the efferent neuronal system within the inner ear, it could affect susceptibility to noise‐induced hearing loss or presbycusis. It is feasible that the natural aging process combined with neurodegenerative changes intrinsic to Parkinson's disease might interfere with cochlear transduction mechanisms, thus anticipating presbycusis. © 2012 Movement Disorder Society
Self‐adjoint singularly perturbed boundary value problems: an adaptive variational approach
Authors: Khuri S.A. , Sayfy A.
Published: October 2012

This study is intended to provide a modified variational algorithm for the numerical solution of a class of self‐adjoint singularly perturbed boundary value problem, which is equally applicable to other classes of problems. The principle of the method lies in the introduction of a mixed piecewise domain decomposition and manipulating the variational iterative approach for tackling this class of problems. The uniform convergence of the technique to the exact solution is demonstrated. Numerical results, computational comparisons, suitable error measures and illustrations are provided to testify efficiently and demonstrate the convergence, efficiency and applicability of the method. Copyright © 2012 John Wiley & Sons, Ltd.
Experiences of Healthcare Provision for Foot Ulceration Occurring in People with Rheumatoid Arthritis
Authors: Firth Jill , Nelson Andrea , Briggs Michelle , Gorecki Claudia
Published: October 2012

Background

Participants with rheumatoid arthritis (RA) report that foot ulceration has an impact on their health‐related quality of life (HRQL) across physical, social and psychological domains. What is not known is how experiences of healthcare provision influence HRQL. The present study set out to map the patent journey while integrating the impact on HRQL.

Methods

A purposive sample of RA patients with open foot ulceration was recruited from podiatry clinics in West Yorkshire (UK) between May 2008 and June 2009. Patients with diabetes were excluded (the impact of foot ulceration in this group is well established). In‐depth interviews were taped and transcribed. A framework approach to data management was used to facilitate a case‐ and theme‐based analysis.

Results

Twenty‐three RA patients (18 female, five male; aged 45–88 years) participated. Two themes and five sub‐themes were identified. The patient journey theme comprised the following sub‐themes: access to care; knowledge acquisition; care pathways and continuity of care. Patient–professional relationships comprised the sub‐themes: therapeutic patient–professional relationships and task‐orientated care. The journey took a highly variable course that was influenced by patient‐specific factors (past experience of ulceration; symptomology; knowledge and self‐efficacy); service‐specific factors (access to care and care pathways) and professional‐specific factors (knowing and trusting someone; holism).

Conclusions

The present study highlights the need for clearer care pathways for patients affected by foot ulceration improved patient education and better coordination of care. Copyright © 2012 John Wiley & Sons, Ltd.
Pompe disease, the must‐not‐miss diagnosis: A report of 3 patients
Authors: Dubrovsky Alberto , Corderi Jose , Karasarides Theodora , Taratuto Ana Lia
Published: October 2012

Introduction: Pompe disease is a progressive and debilitating neuromuscular disorder that presents with a heterogeneous array of signs and symptoms including proximal muscle weakness, respiratory insufficiency, and/or elevated creatine kinase levels. It mimics other neuromuscular disorders, making its diagnosis challenging and often significantly delayed, thereby increasing morbidity and early mortality of the disease. Methods: Three Pompe disease patients are discussed to highlight the challenging path to diagnosis and the common cluster of symptoms that could lead to timely and accurate diagnosis. Results: After significant delays in diagnosis, Pompe disease was diagnosed on the basis of the pattern of proximal weakness. Conclusions: Suspicion and recognition of the characteristic symptoms of Pompe disease may improve both the timing and accuracy of the diagnosis, which will improve clinical outcomes and minimize disease progression. Muscle Nerve, 2013
Study on peroxide vulcanization thermodynamics of ethylene–vinyl acetate copolymer rubber using 2,2,6,6,‐tetramethylpiperidinyloxyl nitroxide
Authors: Posadas Pilar , Fernández‐Torres Alberto , Chamorro Celia , Mora‐Barrantes Irene , Rodríguez Andrés , González Luis , Valentín Juan L
Published: October 2012

A step forward in the understanding of rubber vulcanization with organic peroxides is provided by combining a proper arrangement between polymer, vulcanizing agent and cure conditions. For this purpose, an ethylene–vinyl acetate copolymer with a high content of vinyl acetate (70 mol%) was used since a fully saturated polymer backbone allows its vulcanization via peroxide. For the range of conditions analysed here, it is shown that the predominant process taking place is crosslinking via radical recombination, minimizing or even avoiding undesirable secondary reactions such us polymer degradation. Once conditions had been optimized, peroxide vulcanization was analysed in more depth in the presence of 2,2,6,6‐tetramethylpiperidinyloxyl, which is a mediating stable free radical commonly used in controlled radical polymerization. Consequently, it was possible to differentiate the termination reaction from the initiation and propagation steps, allowing the determination of the enthalpy of formed C–C crosslinks as measured using calorimetry. It was possible to isolate and determine the contribution of the crosslinking pathway from the global vulcanization reaction by means of calorimetric methods at optimum conditions. In fact, this simple methodology could be an important tool for understanding in detail the complex peroxide vulcanization of elastomers since reactions involved in this process determine the final network structure, and thus the final elastic properties of these compounds.
Quantitative mass spectrometry for colorectal cancer proteomics
Authors: Martínez‐Aguilar Juan , Chik Jenny , Nicholson Judith , Semaan Crystal , McKay Matthew J. , Molloy Mark P.
Published: October 2012

This review documents the uses of quantitative MS applied to colorectal cancer (CRC) proteomics for biomarker discovery and molecular pathway profiling. Investigators are adopting various labeling and label‐free MS approaches to quantitate differential protein levels in cells, tumors, and plasma/serum. We comprehensively review recent uses of this technology to examine mouse models of CRC, CRC cell lines, their secretomes and subcellular fractions, CRC tumors, CRC patient plasma/serum, and stool samples. For biomarker discovery these approaches are uncovering proteins with potential diagnostic and prognostic utility, while in vitro cell culture experiments are characterizing proteomic and phosphoproteomic responses to disrupted signaling pathways due to mutations or to inhibition of drugable enzymes.
Anti‐inflammatory Effects of the Zingiber officinale roscoe Constituent 12‐Dehydrogingerdione in Lipopolysaccharide‐stimulated Raw 264.7 Cells
Authors: Han Young ah , Song Chang woo , Koh Woo suk , Yon Gyu hwan , Kim Young sup , Ryu Shi yong , Kwon Hoon jeong , Lee Kyu hong
Published: October 2012

Ginger has long been used worldwide as a spice, seasoning, and wine and is also used as a traditional medicine. There have been no previous studies of the potential beneficial effects of the ginger constituent 12‐dehydrogingerdione (12‐DHGD). We investigated the anti‐inflammatory effect of 12‐DHGD on lipopolysaccharide (LPS)‐stimulated Raw 264.7 cells. The cytotoxicity of 12‐DHGD was measured using the MTT assay, and production of prostaglandin E2 (PGE2) and the inflammatory cytokines interleukin (IL)‐1β, IL‐6, and tumor necrosis factor (TNF)‐α was measured by ELISA. Production of nitric oxide (NO) was measured using Griess reagent and expression of cyclooxygenase‐2 (COX‐2) and inducible NO (iNOS) enzymes was assessed by reverse transcriptase‐polymerase chain reaction. Treatment of Raw 264.7 cells with 12‐DHGD significantly inhibited LPS‐stimulated production of NO (at 12‐DHGD concentrations of 150 and 200 ng/ml), IL‐6 (at 50, 100, 150, and 200 ng/ml), and PGE2 (at 200 ng/ml). Consistent with the effects on NO and PGE2 production, 12‐DHGD treatment also inhibited the LPS‐stimulated increase in iNOS and COX‐2 mRNA levels. However, 12‐DHGD did not affect production of IL‐1β or TNF‐α in response to LPS. 12‐DHGD, a constituent of ginger, is a potent inhibitor of proinflammatory mediator production in Raw 264.7 macrophage cells. Copyright © 2012 John Wiley & Sons, Ltd.
LONG‐TERM VEGETATION DYNAMICS AFTER HIGH‐DENSITY SEEDLING ESTABLISHMENT: IMPLICATIONS FOR RIPARIAN RESTORATION AND MANAGEMENT
Authors: Bunting D. P. , Kurc S. , Grabau M.
Published: October 2012

Human disturbances have contributed to the deterioration of many western US rivers in the past century. Cottonwood‐willow communities, present historically along the Colorado River, protect watersheds and provide wildlife habitat, but are now among the most threatened forests. As a result, restoration efforts have increased to re‐establish and maintain cottonwood‐willow stands. While successful establishment has been observed using multiple strategies with varying investments, few projects are evaluated to quantify efficacy and determine long‐term sustainability. We monitored a seeded cottonwood‐willow site over a five‐year period beginning in 2007, with particular interest in how density affected vegetation diversity and stand structure over time. Fremont cottonwood (Populus fremontii) and volunteer tamarisk (Tamarix ramosissma) were the only abundant riparian trees at the site after one year. P. fremontii, compared to T. ramosissma, had higher growth rates, lower mortality, and dominated overstory and total cover each year. Vegetation diversity decreased from 2007–2009, but was similar from 2009–2011 as a result of decreased herbaceous and increased shrub species richness. Diversity was highest in the lowest density class (1‐12 stems/m2), but similar among all other classes (13–24, 25–42, 43+). High initial woody species densities resulted in single‐stemmed trees with depressed terminal and radial growths. Allometry, relating height to DBH at different densities, could prove to be an important tool for long‐term restoration management and studying habitat suitability. Understanding long‐term trends at densely‐planted or seeded sites can benefit restoration managers who aim to establish specific community structure and vegetation diversity for wildlife habitat. Copyright © 2012 John Wiley & Sons, Ltd.
Early termination of a two‐stage study to develop and validate a panel of biomarkers
Authors: Koopmeiners Joseph S. , Vogel Rachel Isaksson
Published: October 2012

Two‐stage designs to develop and validate a panel of biomarkers present a natural setting for the inclusion of stopping rules for futility in the event of poor preliminary estimates of performance. We consider the design of a two‐stage study to develop and validate a panel of biomarkers where a predictive model is developed using a subset of the samples in stage 1 and the model is validated using the remainder of the samples in stage 2. First, we illustrate how we can implement a stopping rule for futility in a standard, two‐stage study for developing and validating a predictive model where samples are separated into a training sample and a validation sample. Simulation results indicate that our design has type I error rate and power similar to the fixed‐sample design but with a substantially reduced sample size under the null hypothesis. We then illustrate how we can include additional interim analyses in stage 2 by applying existing group sequential methodology, which results in even greater savings in the number of samples required under both the null and the alternative hypotheses. Our simulation results also illustrate that the operating characteristics of our design are robust to changes in the underlying marker distribution. Copyright © 2012 John Wiley & Sons, Ltd.
Clinical and biological features at diagnosis in mitochondrial fatty acid beta‐oxidation defects: a French pediatric study of 187 patients
Authors: Baruteau Julien , Sachs Philippe , Broué Pierre , Brivet Michèle , Abdoul Hendy , Vianey‐Saban Christine , Ogier de Baulny Hélène
Published: October 2012

Introduction

Mitochondrial fatty acid β‐oxidation defects (FAODs) are a group of severe inherited metabolic diseases, most of which can be treated with favorable prognosis following diagnosis. A description of the broad range of phenotypes resulting from these defects remains incomplete, and for this study, we sought to investigate the semiology at diagnosis in a country without a newborn screening program for FAODs.

Methods

Using a retrospective French multicentre study, we analyzed 187 children aged <6 years at diagnosis with FAOD confirmed by enzymatic and/or molecular analyses. Clinical and biological parameters at diagnosis were assessed to screen liver, heart, neurological, and muscle symptoms. Information concerning the long‐term prognosis was also collected.

Results

Predominant hepatic symptoms were observed in 89 % of patients regardless of the underlying defect. The most frequent symptoms observed were hepatomegaly (92 %), increased blood alanine aminotransferase (ALAT) level (82 %), and steatosis (88 %). Other frequent features included Reye syndrome (49 %), increased gamma‐glutamyltranspeptidase (GGT) (37 %), and liver failure (27 %). Extrahepatic features were often associated in the foreground. Hypoglycemia (75 %), neurological (64 %), muscle (61 %), or cardiac features (55 %) [as either cardiomyopathy (47 %) or arrhythmias (31 %)] were frequently documented. Hemodynamic events (41 %) were represented by shock (31 %) or sudden death (35 %). Hyperammonemia (73 %) and hyperlactacidemia (57 %) were the two main biochemical features. Total, very‐long‐chain acyl‐CoA dehydrogenase (VLCADD), long‐chain 3‐hydroxyacylCoA dehydrogenase (LCHADD), and medium‐chain acyl‐CoA dehydrogenase (MCADD) deficiency mortality rates were 48 %, 60 %, 63 %, and 20 % respectively.

Conclusion

This study presents clinical features of a large cohort of patients with FAODs in a country without neonatal screening for FAODs. Our results highlight liver as the main organ involved at diagnosis regardless of age at diagnosis, classical phenotype (i.e., cardiac, hepatic, or muscular), or enzyme deficiency. Although steatosis may be observed in various inherited metabolic defects, it is a reliable indicator of FAOD and should prompt systematic screening when the diagnosis is suspected. The poor long‐term prognoses reported are a strong argument for inclusion of FAODs in newborn screening programs.
Prediction of the functional effect of novel SLC25A13 variants using a S. cerevisiae model of AGC2 deficiency
Authors: Wongkittichote Parith , Tungpradabkul Sumalee , Wattanasirichaigoon Duangrurdee , Jensen Laran T.
Published: October 2012

AGC2, a member of the mitochondrial carrier protein family, is as an aspartate‐glutamate carrier and is important for urea synthesis and the maintenance of the malate‐aspartate shuttle. Mutations in SLC25A13, the gene encoding AGC2, result in two age dependent disorders: neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) and type II citrullinemia (CTLN2). The clinical features of CTLN2 are very similar to those of other urea cycle disorders making a clear diagnosis difficult. Analysis of the SLC25A13 gene sequence can provide a definitive diagnosis, however the predictive value of DNA sequencing requires that the disease association of variants be characterized. We utilized the yeast Saccharomyces cerevisiae lacking AGC1 as a model system to study the effect on the function of AGC2 variants and confirmed that this system is capable of distinguishing between AGC2 variants with normal (p.Pro632Leu) or impaired function (p.Gly437Glu, p.Gly531Asp, p.Thr546Met, p.Leu598Arg and p.Glu601Lys). Three novel AGC2 genetic variants, p.Met1? (c.2T>C), p.Pro502Leu (c.1505C>T), and p.Arg605Gln (c.1814G>A) were investigated and our analysis revealed that p.Pro502Leu and p.Arg605Gln substitutions in the AGC2 protein were without effect and these variants were fully functional. The p.Met1? mutant is capable of expressing a truncated p.Met1_Phe34del AGC2 variant, however this protein is not functional due to disruptions in a calcium binding EF hand as well as incorrect intracellular localization. Our study demonstrates that the characterization of AGC2 expressed in yeast cells is a powerful technique to investigate AGC2 variants, and this analysis should aid in establishing the disease association of novel variants.
Biofuel from plant biomass
Authors: Kerckhoffs Huub , Renquist Richard
Published: October 2012

Plant biomass can be used for multiple forms of bioenergy, and there is a very large potential supply, depending on which global assessment is most accurate in terms of land area that could be available for biomass production. The most suitable plant species must be identified before the potential biomass production in a particular region can be quantified. This in turn depends on the degree of climatic adaptation by those species. In the range of climates present in New Zealand, biomass crop growth has less restriction due to water deficit or low winter temperature than in most world regions. Biomass production for energy use in New Zealand would be best utilised as transport fuel since 70 % of the country’s electricity generation is already renewable, but nearly all of its transport fossil fuel is imported. There is a good economic development case for transport biofuel production using waste streams and biomass crops. This review identified the most suitable crop species and assessed their production potential for use within the climatic range present in New Zealand. Information from published work was used as a basis for selecting appropriate crops in a 2-year selection and evaluation process. Where there were knowledge gaps, the location-specific selections were further evaluated by field measurements. The data presented have superseded much of the speculative information on the suitability of species for the potential development of a biofuel industry in New Zealand.
Stimulation of Escherichia coli DNA damage inducible DNA helicase DinG by the single‐stranded DNA binding protein SSB
Authors: Cheng Zishuo , Caillet Aimee , Ren Binbin , Ding Huangen
Published: October 2012

DinG
and
SSB
bind by cosedimentation in solution (View interaction)
Near‐cognate suppression of amber, opal and quadruplet codons competes with aminoacyl‐tRNAPyl for genetic code expansion
Authors: O'Donoghue Patrick , Prat Laure , Heinemann Ilka U. , Ling Jiqiang , Odoi Keturah , Liu Wenshe R. , Söll Dieter
Published: October 2012

Over 300 amino acids are found in proteins in nature, yet typically only 20 are genetically encoded. Reassigning stop codons and use of quadruplet codons emerged as the main avenues for genetically encoding non‐canonical amino acids (NCAAs). Canonical aminoacyl‐tRNAs with near‐cognate anticodons also read these codons to some extent. This background suppression leads to ‘statistical protein’ that contains some natural amino acid(s) at a site intended for NCAA. We characterize near‐cognate suppression of amber, opal and a quadruplet codon in common Escherichia coli laboratory strains and find that the PylRS/tRNAPyl orthogonal pair cannot completely outcompete contamination by natural amino acids.
Partial Acceptor Photobleaching-Based Quantitative FRET Method Completely Overcoming Emission Spectral Crosstalks
Authors: Li Huali , Yu Huaina , Chen Tongsheng
Published: October 2012

Based on the quantitative fluorescence resonance energy transfer (FRET) method named PbFRET we reported recently, we herein developed a partial acceptor photobleaching-based quantitative FRET algorithm named B-PbFRET method. B-PbFRET overcomes not only the acceptor excitation crosstalk and donor emission spectral crosstalk but also the acceptor emission spectral crosstalk that harasses previous methods including fluorescence lifetime (FLIM), fluorescence recovery of donor after acceptor photobleaching, and acceptor sensitized emission (SE)-based methods. B-PbFRET method is implemented by simultaneously measuring the fluorescence intensity of both donor and acceptor channels at donor excitation before and after partial acceptor photobleaching, and it can directly measure the FRET efficiency (E) without any verified references. Based on the theoretical analysis of B-PbFRET, we also developed a more straightforward correction method named C-PbFRET to obtain the absolute E from the value measured by PbFRET for a given donor-acceptor pair. We validated both B-PbFRET and C-PbFRET methods by measuring the E of two linked constructs, 18AA and SCAT3 proteins, in single living cells, and our data demonstrated that both B-PbFRET and C-PbFRET methods can directly measure the absolute E of the linked constructs inside living cells under different degrees of acceptor emission spectral crosstalk.
Polarization and direction of arrival of Jovian quasiperiodic bursts observed by Cassini
Authors: Kimura T. , Cecconi B. , Zarka P. , Kasaba Y. , Tsuchiya F. , Misawa H. , Morioka A.
Published: October 2012

Jovian quasiperiodic (QP) radio bursts are suspected to be associated with relativistic particle accelerations occurring with a quasiperiodicity between a few minutes and a few tens of minutes in Jupiter's polar magnetosphere. Understanding the excitation and propagation of QP bursts could help us to better understand this periodic energization process. A first necessary step is to measure the wave mode, source location, and directivity of QP bursts. For that purpose, we performed a statistical analysis of goniopolarimetric measurements of QP bursts made with the Radio and Plasma Wave Science investigation (RPWS) onboard Cassini spacecraft during the Jupiter flyby of 2000–2001. We studied two groups of QP bursts on 22 and 23 December 2000, and we found consistent source directions about 50 RJ north of Jupiter with an error bar ≤20 RJ. Statistics of the Stokes parameters indicate that QP bursts are partially left‐handed polarized (V > 0, Q, U < 0). Together with the direction finding results, these polarization statistics imply that QP bursts observed from low latitudes are L‐O mode waves which have been excited in the northern polar source, have propagated toward high latitudes, and then got refracted equatorward in the magnetosheath. Dependence of the Stokes parameters on the longitude indicates that QP bursts are excited within a particular phase range of the planetary rotation, when the system III longitude of the sub‐solar point is between 260° and 480°. This implies that QP radio bursts and associated particle accelerations always occur within the same rotational sector, suggesting the existence of a recurrent magnetospheric disturbance at the planetary rotation period. Finally, we propose a possible scenario for the generation and propagation of QP bursts by combining the results of the present study with those of other recent observational and theoretical studies.
Underlying structural control of small‐scale faults and fractures in West Candor Chasma, Mars
Authors: Birnie C. , Fueten F. , Stesky R. , Hauber E.
Published: October 2012

Orientations of small‐scale faults and fractures within the interior layered deposits of West Candor Chasma were measured to investigate what information about the geologic history of Valles Marineris they can contribute. Deformational features were separated into six categories based on morphology and their orientations were analyzed. The elevations at which the deformational features formed are recorded, as a proxy for stratigraphic level. Deformational features occur over a continuous range of elevations and display regionally consistent preferred orientations, indicating their formation was controlled by a regional stress regime. The two most abundant preferred orientations of ∼35° and ∼110° are approximately parallel to the chasma walls and the inferred underlying normal faults. The alignment of three populations of small faults at 140°, consistent with the morphology of release faults, indicates a large‐scale fault underlying the southeastern border of Ceti Mensa. The preferred orientations imply these small‐scale deformational features formed from a continuation of the same imposed stresses responsible for the formation of Valles Marineris, indicating these stresses existed past the formation of the interior layered deposits. The origins of a fourth preferred orientation of 70° is less clear but suggests the study area has undergone at least two periods of deformation.
Transient infiltration from ephemeral streams: A field experiment at the reach scale
Authors: Batlle‐Aguilar Jordi , Cook Peter G.
Published: October 2012

An infiltration experiment at the stream reach scale was performed to estimate infiltration rates beneath an ephemeral, losing stream during streamflow events. At a time when the stream was dry, a 7 m stream section was dammed upstream and downstream using metal sheets. During a 5 day period water was pumped into the isolated section of the stream, and the surface water level was maintained at three successive increasing stages. The infiltration rate at each water level was thereby equal to the pumping rate required to maintain that water level. The advantages of the method are that it samples a much greater area than traditional methods and provides information on infiltration through stream banks as well as through the streambed. Experimental results provide insight into transient infiltration and recharge processes beneath ephemeral streams. Although the experiment continued for 5 days, infiltration during the first hour accounted for 19% of the total infiltration. High transient infiltration rates were also observed following each increase in stream stage. Experimental infiltration rates were used to calibrate a two‐dimensional model developed within Hydrus, which was subsequently used to estimate infiltration associated with a natural flow event in the same stream reach. During the natural flow event, the total infiltration was 33% greater than would have been estimated assuming steady state infiltration rates. Dry antecedent moisture content controls the transient infiltration rate and hence increases the total infiltrated volume during flow events, but it does not increase the aquifer recharge.
Effective models for CO2 migration in geological systems with varying topography
Authors: Gasda Sarah E. , Nilsen Halvor M. , Dahle Helge K. , Gray William G.
Published: October 2012

Geological CO2 sequestration relies on a competent sealing layer, or caprock, that bounds the formation top and prevents vertical migration of CO2 and brine. Modeling studies have shown that caprock topography, or roughness, can significantly decrease updip migration speed of CO2 and increase structural trapping. Caprock roughness can be characterized at different spatial scales. For instance, regional‐scale features such as domes, traps, and spill points can be detected in seismic surveys and have been shown to affect large‐scale migration patterns. However, structural and topographical variability, known as rugosity, exists below seismic detection limits but can be measured at the scale of centimeters and meters using LiDAR scanning of formation outcrops. Little is known about the actual impact of structural rugosity on CO2 plume migration. Practically speaking, given the large scales required to model commercial scale CO2 storage projects and the limitations on computational power, only seismic‐scale caprock topography can be resolved using standard discretization techniques. Therefore, caprock variability that exists below the model resolution scale is defined as subscale and must be handled by upscaling. In this paper we derive effective equations for CO2 migration that include the impact of fine‐scale variability in caprock topography using static equilibrium upscaling, an approach that is adapted for the vertical equilibrium modeling framework. The effective equations give estimates of the impact of rugosity on CO2 plume migration and trapping in large‐scale systems.
Linker histone subtypes and their allelic variants
Authors: Kowalski Andrzej , Pałyga Jan
Published: October 2012

Members of histone H1 family bind to nucleosomal and linker DNA to assist in stabilization of higher‐order chromatin structures. Moreover, histone H1 is involved in regulation of a variety of cellular processes by interactions with cytosolic and nuclear proteins. Histone H1, composed of a series of subtypes encoded by distinct genes, is usually differentially expressed in specialized cells and frequently non‐randomly distributed in different chromatin regions. Moreover, a role of specific histone H1 subtype might be also modulated by post‐translational modifications and/or presence of polymorphic isoforms. While the significance of covalently modified histone H1 subtypes has been partially recognized, much less is known about the importance of histone H1 polymorphic variants identified in various plant and animal species, and human cells as well. Recent progress in elucidating amino acid composition‐dependent functioning and interactions of the histone H1 with a variety of molecular partners indicates a potential role of histone H1 polymorphic variation in adopting specific protein conformations essential for chromatin function. The histone H1 allelic variants might affect chromatin in order to modulate gene expression underlying some physiological traits and, therefore could modify the course of diverse histone H1‐dependent biological processes. This review focuses on the histone H1 allelic variability, and biochemical and genetic aspects of linker histone allelic isoforms to emphasize their likely biological relevance.
Substrates of Factor XIII-A: roles in thrombosis and wound healing
Authors: Richardson Victoria R. , Cordell Paul , Standeven Kristina F. , Carter Angela M.
Published: October 2012

FXIII (Factor XIII) is a Ca2+-dependent enzyme which forms covalent ϵ-(γ-glutamyl)lysine cross-links between the γ-carboxy-amine group of a glutamine residue and the ϵ-amino group of a lysine residue. FXIII was originally identified as a protein involved in fibrin clot stabilization; however, additional extracellular and intracellular roles for FXIII have been identified which influence thrombus resolution and tissue repair. The present review discusses the substrates of FXIIIa (activated FXIII) involved in thrombosis and wound healing with a particular focus on: (i) the influence of plasma FXIIIa on the formation of stable fibrin clots able to withstand mechanical and enzymatic breakdown through fibrin–fibrin cross-linking and cross-linking of fibrinolysis inhibitors, in particular α2-antiplasmin; (ii) the role of intracellular FXIIIa in clot retraction through cross-linking of platelet cytoskeleton proteins, including actin, myosin, filamin and vinculin; (iii) the role of intracellular FXIIIa in cross-linking the cytoplasmic tails of monocyte AT1Rs (angiotensin type 1 receptors) and potential effects on the development of atherosclerosis; and (iv) the role of FXIIIa on matrix deposition and tissue repair, including cross-linking of extracellular matrix proteins, such as fibronectin, collagen and von Willebrand factor, and the effects on matrix deposition and cell–matrix interactions. The review highlights the central role of FXIIIa in the regulation of thrombus stability, thrombus regulation, cell–matrix interactions and wound healing, which is supported by observations in FXIII-deficient humans and animals.
Aberrant expression of c-Jun in glioblastoma by internal ribosome entry site (IRES)-mediated translational activation
Authors: Blau Lior , Knirsh Revital , Ben-Dror Iris , Oren Sivan , Kuphal Silke , Hau Peter , Proescholdt Martin , Bosserhoff Anja-Katrin , Vardimon Lily
Published: October 2012

Although the protooncogene c-Jun plays a critical role in cell proliferation, cell death, and malignant transformation, DNA microarray screens have identified only a few human cancer types with aberrant expression of c-Jun. Here, we show that c-Jun accumulation is robustly elevated in human glioblastoma and that this increase contributes to the malignant properties of the cells. Most importantly, the increase in c-Jun protein accumulation occurs with no corresponding increase in c-Jun mRNA or the half-life of the c-Jun protein but, rather, in the translatability of the transcript. The c-Jun 5′UTR harbors a potent internal ribosomal entry site (IRES) with a virus-like IRES domain that directs cap-independent translation in glioblastoma cells. Accumulation of c-Jun is not dependent on MAPK activity but can be stimulated by a cytoskeleton-dependent pathway. Our findings provide evidence that human c-Jun is an IRES-containing cellular transcript that contributes to cancer development through translational activation. This previously undescribed mechanism of c-Jun regulation might also be relevant to other types of human cancer and offers unique potential targets for therapy.
Collective mesendoderm migration relies on an intrinsic directionality signal transmitted through cell contacts
Authors: Dumortier Julien G. , Martin Sandro , Meyer Dirk , Rosa Frederic M. , David Nicolas B.
Published: October 2012

Collective cell migration is key to morphogenesis, wound healing, or cancer cell migration. However, its cellular bases are just starting to be unraveled. During vertebrate gastrulation, axial mesendoderm migrates in a group, the prechordal plate, from the embryonic organizer to the animal pole. How this collective migration is achieved remains unclear. Previous work has suggested that cells migrate as individuals, with collective movement resulting from the addition of similar individual cell behavior. Through extensive analyses of cell trajectories, morphologies, and polarization in zebrafish embryos, we reveal that all prechordal plate cells show the same behavior and rely on the same signaling pathway to migrate, as expected if they do so individually. However, by using cell transplants, we demonstrate that prechordal plate migration is a true collective process, as isolated cells do not migrate toward the animal pole. They are still polarized and motile but lose directionality. Directionality is restored upon contact with the endogenous prechordal plate. This contact dependent orientation relies on E-cadherin, Wnt-PCP signaling, and Rac1. Importantly, groups of cells also need contact with the endogenous plate to orient correctly, showing an instructive role of the plate in establishing directionality. Overall, our results lead to an original model of collective migration in which directional information is contained within the moving group rather than provided by extrinsic cues, and constantly maintained in cells by contacts with their neighbors. This self-organizing model could account for collective invasion of new territories, as observed in cancer strands, without requirement for any attractant in the colonized tissue.
Adolescents’ risk-taking behavior is driven by tolerance to ambiguity
Authors: Tymula Agnieszka , Rosenberg Belmaker Lior A. , Roy Amy K. , Ruderman Lital , Manson Kirk , Glimcher Paul W. , Levy Ifat
Published: October 2012

Adolescents engage in a wide range of risky behaviors that their older peers shun, and at an enormous cost. Despite being older, stronger, and healthier than children, adolescents face twice the risk of mortality and morbidity faced by their younger peers. Are adolescents really risk-seekers or does some richer underlying preference drive their love of the uncertain? To answer that question, we used standard experimental economic methods to assess the attitudes of 65 individuals ranging in age from 12 to 50 toward risk and ambiguity. Perhaps surprisingly, we found that adolescents were, if anything, more averse to clearly stated risks than their older peers. What distinguished adolescents was their willingness to accept ambiguous conditions—situations in which the likelihood of winning and losing is unknown. Though adults find ambiguous monetary lotteries undesirable, adolescents find them tolerable. This finding suggests that the higher level of risk-taking observed among adolescents may reflect a higher tolerance for the unknown. Biologically, such a tolerance may make sense, because it would allow young organisms to take better advantage of learning opportunities; it also suggests that policies that seek to inform adolescents of the risks, costs, and benefits of unexperienced dangerous behaviors may be effective and, when appropriate, could be used to complement policies that limit their experiences.
Targeted microRNA expression in dairy cattle directs production of β-lactoglobulin-free, high-casein milk
Authors: Jabed Anower , Wagner Stefan , McCracken Judi , Wells David N. , Laible Goetz
Published: October 2012

Milk from dairy cows contains the protein β-lactoglobulin (BLG), which is not present in human milk. As it is a major milk allergen, we wished to decrease BLG levels in milk by RNAi. In vitro screening of 10 microRNAs (miRNAs), either individually or in tandem combinations, identified several that achieved as much as a 98% knockdown of BLG. One tandem construct was expressed in the mammary gland of an ovine BLG-expressing mouse model, resulting in 96% knockdown of ovine BLG in milk. Following this in vivo validation, we produced a transgenic calf, engineered to express these tandem miRNAs. Analysis of hormonally induced milk from this calf demonstrated absence of BLG and a concurrent increase of all casein milk proteins. The findings demonstrate miRNA–mediated depletion of an allergenic milk protein in cattle and validate targeted miRNA expression as an effective strategy to alter milk composition and other livestock traits.
Triggering the measles virus membrane fusion machinery
Authors: Brindley Melinda A. , Takeda Makoto , Plattet Philippe , Plemper Richard K.
Published: October 2012

Paramyxoviruses contain glycoprotein fusion machineries that mediate membrane merger for infection. The molecular framework and mechanistic principles governing receptor-induced triggering of the machinery remain unknown. Using measles virus (MeV) fusion complexes, we demonstrate that receptor binding to only one dimer of the tetrameric attachment protein (H) dimer-of-dimers induces fusion-protein (F) triggering; receptor binding and F triggering can be communicated across the dimer–dimer interface of H; and the physical integrity of the tetramer is maintained during fusion. The central MeV H ectodomain stalk region requires structural flexibility for activation of F, and alanine substitutions in this section, physical stress, or exposure of H to soluble ligands trigger conformational rearrangements in native H tetramers. Binding of soluble receptor to H is sufficient to initiate refolding of F, underscoring the physiological significance of this rearrangement of the H tetramer. These data outline a model of the triggering of the physiological MeV fusion machinery in which unilateral receptor binding to one dimer pair in the H tetramer is sufficient to induce a reorganization of H that affects the conformation of the central stalk section, severing interactions between H and the F trimer and activating refolding of F.
In vitro reconstitution of the ordered assembly of the endosomal sorting complex required for transport at membrane-bound HIV-1 Gag clusters
Authors: Carlson Lars-Anders , Hurley James H.
Published: October 2012

Most membrane-enveloped viruses depend on host proteins of the endosomal sorting complex required for transport (ESCRT) machinery for their release. HIV-1 is the prototypic ESCRT-dependent virus. The direct interactions between HIV-1 and the early ESCRT factors TSG101 and ALIX have been mapped in detail. However, the full pathway of ESCRT recruitment to HIV-1 budding sites, which culminates with the assembly of the late-acting CHMP4, CHMP3, CHMP2, and CHMP1 subunits, is less completely understood. Here, we report the biochemical reconstitution of ESCRT recruitment to viral assembly sites, using purified proteins and giant unilamellar vesicles. The myristylated full-length Gag protein of HIV-1 was purified to monodispersity. Myr-Gag forms clusters on giant unilamellar vesicle membranes containing the plasma membrane lipid PI(4,5)P
2
. These Gag clusters package a fluorescent oligonucleotide, and recruit early ESCRT complexes ESCRT-I or ALIX with the appropriate dependence on the Gag PTAP and LYP(X)
n
L motifs. ALIX directly recruits the key ESCRT-III subunit CHMP4. ESCRT-I can only recruit CHMP4 when ESCRT-II and CHMP6 are present as intermediary factors. Downstream of CHMP4, CHMP3 and CHMP2 assemble synergistically, with the presence of both subunits required for efficient recruitment. The very late-acting factor CHMP1 is not recruited unless the pathway is completed through CHMP3 and CHMP2. These findings define the minimal sets of components needed to complete ESCRT assembly at HIV-1 budding sites, and provide a starting point for in vitro structural and biophysical dissection of the system.
Heterosubtypic antibody recognition of the influenza virus hemagglutinin receptor binding site enhanced by avidity
Authors: Lee Peter S. , Yoshida Reiko , Ekiert Damian C. , Sakai Naoki , Suzuki Yasuhiko , Takada Ayato , Wilson Ian A.
Published: October 2012

Continual and rapid mutation of seasonal influenza viruses by antigenic drift necessitates the almost annual reformulation of flu vaccines, which may offer little protection if the match to the dominant circulating strain is poor. S139/1 is a cross-reactive antibody that neutralizes multiple HA strains and subtypes, including those from H1N1 and H3N2 viruses that currently infect humans. The crystal structure of the S139/1 Fab in complex with the HA from the A/Victoria/3/1975 (H3N2) virus reveals that the antibody targets highly conserved residues in the receptor binding site and contacts antigenic sites A, B, and D. Binding and plaque reduction assays show that the monovalent Fab alone can protect against H3 strains, but the enhanced avidity from binding of bivalent IgG increases the breadth of neutralization to additional strains from the H1, H2, H13, and H16 subtypes. Thus, antibodies making relatively low affinity Fab interactions with the receptor binding site can have significant antiviral activity when enhanced by avidity through bivalent interactions of the IgG, thereby extending the breadth of binding and neutralization to highly divergent influenza virus strains and subtypes.
Fine-tuning synaptic plasticity by modulation of Ca
V
2.1 channels with Ca
2+
sensor proteins
Authors: Leal Karina , Mochida Sumiko , Scheuer Todd , Catterall William A.
Published: October 2012

Modulation of P/Q-type Ca
2+
currents through presynaptic voltage-gated calcium channels (Ca
V
2.1) by binding of Ca
2+
/calmodulin contributes to short-term synaptic plasticity. Ca
2+
-binding protein-1 (CaBP1) and Visinin-like protein-2 (VILIP-2) are neurospecific calmodulin-like Ca
2+
sensor proteins that differentially modulate Ca
V
2.1 channels, but how they contribute to short-term synaptic plasticity is unknown. Here, we show that activity-dependent modulation of presynaptic Ca
V
2.1 channels by CaBP1 and VILIP-2 has opposing effects on short-term synaptic plasticity in superior cervical ganglion neurons. Expression of CaBP1, which blocks Ca
2+
-dependent facilitation of P/Q-type Ca
2+
current, markedly reduced facilitation of synaptic transmission. VILIP-2, which blocks Ca
2+
-dependent inactivation of P/Q-type Ca
2+
current, reduced synaptic depression and increased facilitation under conditions of high release probability. These results demonstrate that activity-dependent regulation of presynaptic Ca
V
2.1 channels by differentially expressed Ca
2+
sensor proteins can fine-tune synaptic responses to trains of action potentials and thereby contribute to the diversity of short-term synaptic plasticity.
Protein kinase WNK3 regulates the neuronal splicing factor Fox-1
Authors: Lee A-Young , Chen Wei , Stippec Steve , Self Jon , Yang Fan , Ding Xiaojun , Chen She , Juang Yu-Chi , Cobb Melanie H.
Published: October 2012

We report an action of the protein kinase WNK3 on the neuronal mRNA splicing factor Fox-1. Fox-1 splices mRNAs encoding proteins important in synaptic transmission and membrane excitation. WNK3, implicated in the control of neuronal excitability through actions on ion transport, binds Fox-1 and inhibits its splicing activity in a kinase activity-dependent manner. Phosphorylation of Fox-1 by WNK3 does not change its RNA binding capacity; instead, WNK3 increases the cytoplasmic localization of Fox-1, thereby suppressing Fox-1–dependent splicing. These findings demonstrate a role of WNK3 in RNA processing. Considering the implication of WNK3 and Fox-1 in disorders of neuronal development such as autism, WNK3 may offer a target for treatment of Fox-1–induced disease.
Numerical analysis of key factors for the appearance of grassy ELMs in tokamak plasmas
Authors: Aiba N. , Oyama N.
Published: October 2012

Numerical stability analysis of edge-localized MHD mode is performed to identify the origin of small-amplitude ‘grassy ELMs’ on the basis of current understanding of kinetic effects on ballooning mode stability. These qualitative and quantitative analyses show that short wavelength ballooning mode can play an important role in a grassy ELM stability even when kinetic effects are taken into account. After showing the importance of kinetic effects for discussing grassy ELM physics, impacts of plasma parameters important for realizing a grassy ELM plasma experimentally are investigated numerically from the viewpoint of the edge-localized MHD stability including these kinetic effects. These analyses show that low plasma ellipticity is preferable to realize a grassy ELM plasma due to destabilizing ballooning mode by preventing access to the second stability region of the ballooning mode.