bluuebunny/crossref_metadata_2025 huggingface dataset:
Children's and adolescents’ tolerance for divergent beliefs: Exploring the cognitive and affective dimensions of moral conviction in our youth
Authors: Wright Jennifer C.
Published: September 2011

Moral conviction predicts interpersonal tolerance in adults, but its role in children and adolescents is not as well understood. This study measured moral conviction for a variety of issues along two separate dimensions – cognitive and affective – in children and adolescents (4th–12th grade). Results showed that, like adults, when children and adolescents view an issue as moral, this is strongly predictive of both age groups’ discomfort with divergent beliefs. But only for adolescents, and not children, did moral conviction play a role in that discomfort, as had previously been found with adults. The context in which the divergent beliefs were encountered also mattered, but more for adolescents than for children – both groups were most comfortable with divergent beliefs when they were encountered in distal relations.
Dynamic Loading on Turbofan Blades Due to Bird-Strike
Authors: Sinha Sunil K. , Turner Kevin E. , Jain Nitesh
Published: September 2011

In the present paper, a hydrodynamic bird material model made up of water and air mixture is developed, which produces good correlation with the measured strain-gauge test data in a panel test. This parametric bird projectile model is used to generate the time-history of the transient dynamic loads on the turbofan engine blades for different size birds impacting at varying span locations of the fan blade. The problem is formulated in 3D vector dynamics equations using a nonlinear trajectory analysis approach. The analytical derivation captures the physics of the slicing process by considering the incoming bird in the shape of a cylindrical impactor as it comes into contact with the rotating fan blades modeled as a pretwisted plate with a camber. The contact-impact dynamic loading on the airfoil produced during the bird-strike is determined by solving the coupled nonlinear dynamical equations governing the movement of the bird-slice in time-domain using a sixth-order Runge-Kutta technique. The analytically predicted family of load time-history curves enables the blade designer to readily identify the critical impact location for peak dynamic loading condition during the bird-ingestion tests mandated for certification by the regulatory agencies.
Comparison of the self-cleaning effects and electrical characteristics of BeO and Al2O3 deposited as an interface passivation layer on GaAs MOS devices
Authors: Yum J. H. , Akyol T. , Ferrer D. A. , Lee J. C. , Banerjee S. K. , Lei M. , Downer M. , Hudnall Todd. W. , Bielawski C. W. , Bersuker G.
Published: September 2011

Beryllium oxide (BeO) is a promising dielectric because of its high energy bandgap (10.6 eV) and short Be and O atom bonds and its excellent electrical insulating characteristics and high thermal stability. In a previous study, the authors showed that BeO grown by atomic layer deposition (ALD) as a gate dielectric on Si and GaAs substrates has excellent electrical and physical characteristics. In this work, we used monochromatic x-ray photoelectron spectroscopy (XPS) and electrical analysis to compare the ability of ALD BeO and Al2O3 to reduce the surface oxide on GaAs substrates. High resolution XPS shows that the BeO reduced surface oxide more efficiently than Al2O3 and that the capacitance-voltage characteristics correspond with the XPS results. In addition, ALD BeO exhibits less interfacial oxide growth after post-deposition annealing and a more efficient suppression of the leakage current
China Aims to Turn Tide Against Toxic Lake Pollution
Authors: Stone Richard
Published: September 2011

Restoring Taihu, China's third largest freshwater lake, to a healthy state will be a challenge akin to ongoing efforts to bring polluted Lake Erie back from the near-dead.
Tickets, Please
Authors: Rytting Erik
Published: September 2011

An apolipoprotein E peptide fragment facilitates the passage of therapeutic liposomes into cells of the blood-brain barrier.
Development of a Poliovirus Neutralization Test with Poliovirus Pseudovirus for Measurement of Neutralizing Antibody Titer in Human Serum
Authors: Arita Minetaro , Iwai Masae , Wakita Takaji , Shimizu Hiroyuki
Published: September 2011

In the Global Polio Eradication Initiative, laboratory diagnosis plays a critical role by isolating and identifying poliovirus (PV) from the stool samples from acute flaccid paralysis (AFP) cases. In recent years, reestablishment of PV circulation in countries where PV was previously eliminated has occurred because of decreased herd immunity, possibly due to poor vaccination coverage. To monitor the vulnerability of countries to PV circulation, surveillance of neutralizing-antibody titers against PV in susceptible populations is essential in the end game of the polio eradication program. In this study, we have developed a PV neutralization test with type 1, 2, and 3 PV pseudoviruses to determine the neutralizing-antibody titer against PV in human serum samples. With this test, the neutralizing-antibody titer against PV could be determined within 2 days by automated interpretation of luciferase signals without using infectious PV strains. We validated the pseudovirus PV neutralization test with 131 human serum samples collected from a wide range of age groups (ages 1 to >60 years) by comparison with a conventional neutralization test. We found good correlation in the neutralizing-antibody titers determined by these tests. These results suggest that a pseudovirus PV neutralization test would serve as a safe and simple procedure for the measurement of the neutralizing-antibody titer against PV.
Utility of Immunoblotting for Early Diagnosis of Toxoplasmosis Seroconversion in Pregnant Women
Authors: Jost C. , Touafek F. , Fekkar A. , Courtin R. , Ribeiro M. , Mazier D. , Paris L.
Published: September 2011

Congenital transmission of
Toxoplasma gondii
occurs mainly when a mother acquires the infection for the first time during pregnancy. It was recently shown that although early treatment of the primary infection during pregnancy has little or no impact on the fetomaternal transmission rate, it does reduce the incidence of sequelae in infected infants. Seroconversion is defined by the appearance of IgG. Commercial reagents continue to vary considerably in detecting low concentrations of antibodies, as during early seroconversion. We compared two routinely used immunoassays (IA) (Platelia and Elecsys Toxo IgG) and an indirect immunofluorescence assay (IIF) with a qualitative test based on immunoblot analysis (Toxo II IgG) (IB) to assess their abilities to diagnose seroconversion at its earliest stages. This prospective study was carried out between January and November 2010. It included 39 pregnant women with monthly follow-up who seroconverted during pregnancy. On first sera that were IgM positive but IgG negative (or equivocal) as detected by IA, IB diagnosed seroconversion twice as often as IIF (26/39 [66.7%] versus 13/39 [33.3%];
P
< 0.001; χ
2
test). Serum samples were retaken 2 to 5 weeks later for the other 13 cases (IgG negative by IB on first serum). Seroconversion was demonstrated as follows: IB for 5 cases where IA remained negative or equivocal, IB and IIF for 5 cases where IA remained negative or equivocal, IA for 2 cases, and no method for 1 case (a third sample was necessary). In summary, IB permitted toxoplasmosis seroconversion diagnosis before other means in 92.3% of cases (36/39) and thus earlier therapeutic intervention.
Perirectal Swab Surveillance for Clostridium difficile by Use of Selective Broth Preamplification and Real-Time PCR Detection of
tcdB
Authors: Curry Scott R. , Schlackman Jessica L. , Hamilton Travis M. , Henderson Tatianna K. , Brown Nakita T. , Marsh Jane W. , Shutt Kathleen A. , Brooks Maria M. , Pasculle A. William , Muto Carlene A. , Harrison Lee H.
Published: September 2011

Active surveillance testing to identify and isolate asymptomatic carriers of toxigenic
Clostridium difficile
has been limited by the lack of a test that is sensitive, specific, and timely enough to serve as an infection control tool. We tested DNA preamplified from perirectal surveillance specimens in a liquid medium selective for
C. difficile
by using a modified commercial real-time PCR assay. All fermenting specimens were subcultured, and isolates were tested for toxigenicity. Culture-positive toxigenic isolates served as the gold standard for comparison with the broth preamplification/PCR assay. The limit of detection for the assay was 1 CFU. Relative to toxigenic anaerobic culture, the sensitivity, specificity, and positive and negative predictive values of this assay were 70/70 (100.0%), 422/426 (99.1%), 70/74 (94.6%), and 422/422 (100.0%), respectively. These data demonstrate that selective broth preamplification and real-time PCR of perirectal swab specimens constitute a practical approach to the detection of asymptomatic
C. difficile
carriage.
Cross-Reactive HIV-1-Neutralizing Human Monoclonal Antibodies Identified from a Patient with 2F5-Like Antibodies
Authors: Zhu Zhongyu , Qin Haiyan Rebekah , Chen Weizao , Zhao Qi , Shen Xiaoying , Schutte Robert , Wang Yanping , Ofek Gilad , Streaker Emily , Prabakaran Ponraj , Fouda Genevieve G. , Liao Hua-Xin , Owens John , Louder Mark , Yang Yongping , Klaric Kristina-Ana , Moody M. Anthony , Mascola John R. , Scott Jamie K. , Kwong Peter D. , Montefiori David , Haynes Barton F. , Tomaras Georgia D. , Dimitrov Dimiter S.
Published: September 2011

The genes encoding broadly HIV-1-neutralizing human monoclonal antibodies (MAbs) are highly divergent from their germ line counterparts. We have hypothesized that such high levels of somatic hypermutation could pose a challenge for elicitation of the broadly neutralizing (bn) Abs and that identification of less somatically mutated bn Abs may help in the design of effective vaccine immunogens. In a quest for such bn Abs, phage- and yeast-displayed antibody libraries, constructed using peripheral blood mononuclear cells (PBMCs) from a patient with bn serum containing Abs targeting the epitope of the bn MAb 2F5, were panned against peptides containing the 2F5 epitope and against the HIV-1 gp140
JR-FL
. Two MAbs (m66 and m66.6) were identified; the more mutated variant (m66.6) exhibited higher HIV-1-neutralizing activity than m66, although it was weaker than 2F5 in a TZM-bl cell assay. Binding of both MAbs to gp41 alanine substitution mutant peptides required the DKW
664–666
core of the 2F5 epitope and two additional upstream residues (L
660,663
). The MAbs have long (21-residue) heavy-chain third complementarity-determining regions (CDR-H3s), and m66.6 (but not m66) exhibited polyspecific reactivity to self- and non-self-antigens. Both m66 and m66.6 are significantly less divergent from their germ line Ab counterparts than 2F5—they have a total of 11 and 18 amino acid changes, respectively, from the closest VH and Vκ germ line gene products compared to 25 for 2F5. These new MAbs could help explore the complex maturation pathways involved in broad neutralization and its relationship with auto- and polyreactivity and may aid design of vaccine immunogens and development of therapeutics against HIV-1 infection.
Characterization of a Canine Homolog of Human Aichivirus
Authors: Kapoor Amit , Simmonds Peter , Dubovi Edward J. , Qaisar Natasha , Henriquez Jose A. , Medina Jan , Shields Shelly , Lipkin W. Ian
Published: September 2011

Many of our fatal “civilization” infectious diseases have arisen from domesticated animals. Although picornaviruses infect most mammals, infection of a companion animal is not known. Here we describe the identification and genomic characterization of the first canine picornavirus. Canine kobuvirus (CKoV), identified in stool samples from dogs with diarrhea, has a genomic organization typical of a picornavirus and encodes a 2,469-amino-acid polyprotein flanked by 5′ and 3′ untranslated regions. Comparative phylogenetic analysis using various structural and nonstructural proteins of CKoV confirmed it as the animal virus homolog most closely related to human Aichivirus (AiV). Bayesian Markov chain Monte Carlo analysis suggests a mean recent divergence time of CKoV and AiV within the past 20 to 50 years, well after the domestication of canines. The discovery of CKoV provides new insights into the origin and evolution of AiV and the species specificity and pathogenesis of kobuviruses.
Host-Soluble Galectin-1 Promotes HIV-1 Replication through a Direct Interaction with Glycans of Viral gp120 and Host CD4
Authors: St-Pierre Christian , Manya Hiroshi , Ouellet Michel , Clark Gary F. , Endo Tamao , Tremblay Michel J. , Sato Sachiko
Published: September 2011

Sexual transmission of HIV-1 requires virus adsorption to a target cell, typically a CD4+T lymphocyte residing in the lamina propria, beneath the epithelium. To escape the mucosal clearance system and reach its target cells, HIV-1 has evolved strategies to circumvent deleterious host factors. Galectin-1, a soluble lectin found in the underlayers of the epithelium, increases HIV-1 infectivity by accelerating its binding to susceptible cells. By comparison, galectin-3, a family member expressed by epithelial cells and part of the mucosal clearance system, does not perform similarly. We show here that galectin-1 directly binds to HIV-1 in a β-galactoside-dependent fashion through recognition of clusters of N-linked glycans on the viral envelope gp120. Unexpectedly, this preferential binding of galectin-1 does not rely on the primary sequence of any particular glycans. Instead, glycan clustering arising from the tertiary structure of gp120 hinders its binding by galectin-3. Increased polyvalency of a specific ligand epitope is a common strategy for glycans to increase their avidity for lectins. In this peculiar occurrence, glycan clustering is instead exploited to prevent binding of gp120 by galectin-3, which would lead to a biological dead-end for the virus. Our data also suggest that galectin-1 binds preferentially to CD4, the host receptor for gp120. Together, these results suggest that HIV-1 exploits galectin-1 to enhance gp120-CD4 interactions, thereby promoting virus attachment and infection events. Since viral adhesion is a rate-limiting step for HIV-1 entry, modulation of the gp120 interaction with galectin-1 could thus represent a novel approach for the prevention of HIV-1 transmission.
Kaposi's Sarcoma-Associated Herpesvirus Rta Tetramers Make High-Affinity Interactions with Repetitive DNA Elements in the Mta Promoter To Stimulate DNA Binding of RBP-Jk/CSL
Authors: Palmeri Diana , Carroll Kyla Driscoll , Gonzalez-Lopez Olga , Lukac David M.
Published: September 2011

Kaposi's sarcoma-associated herpesvirus (KSHV; also known as human herpesvirus 8 [HHV-8]) is the etiologic agent of Kaposi's sarcoma (KS) and lymphoproliferative diseases. We previously demonstrated that the KSHV lytic switch protein Rta stimulates DNA binding of the cellular RBP-Jk/CSL protein, the nuclear component of the Notch pathway, on Rta target promoters. In the current study, we define the promoter requirements for formation of transcriptionally productive Rta/RBP-Jk/DNA complexes. We show that highly pure Rta footprints 7 copies of a previously undescribed repetitive element in the promoter of the essential KSHV Mta gene. We have termed this element the “CANT repeat.” CANT repeats are found on both strands of DNA and have a consensus sequence of ANTGTAACANT(A/T)(A/T)T. We demonstrate that Rta tetramers make high-affinity interactions (i.e., nM) with 64 bp of the Mta promoter but not single CANT units. The number of CANT repeats, their presence in palindromes, and their positions relative to the RBP-Jk binding site determine the optimal target for Rta stimulation of RBP-Jk DNA binding and formation of ternary Rta/RBP-Jk/DNA complexes. DNA binding and tetramerization mutants of Rta fail to stimulate RBP-Jk DNA binding. Our chromatin immunoprecipitation assays show that RBP-Jk DNA binding is broadly, but selectively, stimulated across the entire KSHV genome during reactivation. We propose a model in which tetramerization of Rta allows it to straddle RBP-Jk and contact repeat units on both sides of RBP-Jk. Our study integrates high-affinity Rta DNA binding with the requirement for a cellular transcription factor in Rta transactivation.
In Silico
Reconstruction of Viral Genomes from Small RNAs Improves Virus-Derived Small Interfering RNA Profiling
Authors: Vodovar Nicolas , Goic Bertsy , Blanc Hervé , Saleh Maria-Carla
Published: September 2011

RNA interference (RNAi) is the essential component of antiviral immunity in invertebrates and plants. One of the landmarks of the antiviral RNAi response is the production of virus-derived small interfering RNA (vsiRNA) from viral double-stranded RNA (dsRNA). vsiRNAs constitute a fragmented image of the viral genome sequence that results from Dicer cleavage. vsiRNA sequence profiling is used extensively as a surrogate to study the antiviral RNAi response by determining the nature of the viral dsRNA molecules exposed to and processed by the RNAi machinery. The accuracy of these profiles depends on the actual viral genome sequence used as a reference to align vsiRNA reads, and the interpretation of inaccurate profiles can be misleading. Using Flock house virus and
Drosophila melanogaster
as a model RNAi-competent organism, we show accurate reconstruction of full-length virus reference sequence from vsiRNAs and prediction of the structure of defective interfering particles (DIs). We developed a Perl script, named Paparazzi, that reconstitutes viral genomes through an iterative alignment/consensus call procedure using a related reference sequence as scaffold. As prevalent DI-derived reads introduce artifacts during reconstruction, Paparazzi eliminates DI-specific reads to improve the quality of the reconstructed genome. Paparazzi constitutes a promising alternative to Sanger sequencing in this context and an effective tool to study antiviral RNAi mechanisms by accurately quantifying vsiRNA along the replicating viral genome. We further discuss Paparazzi as a companion tool for virus discovery as it provides full-length genome sequences and corrects for potential artifacts of assembly.
Human Cytomegalovirus Glycoprotein gO Complexes with gH/gL, Promoting Interference with Viral Entry into Human Fibroblasts but Not Entry into Epithelial Cells
Authors: Vanarsdall Adam L. , Chase Marie C. , Johnson David C.
Published: September 2011

A complex of five human cytomegalovirus virus (HCMV) proteins, gH, gL, UL128, UL130, and UL131 (gH/gL/UL128-131), is essential for virus entry into epithelial cells. We previously showed that gH/gL/UL128-131 expressed in epithelial cells interferes with subsequent HCMV entry into cells. There was no interference with only gH/gL or gB. We concluded that the expression of gH/gL/UL128-131 causes a mislocalization or downregulation of epithelial cell proteins that HCMV requires for entry. In contrast, gH/gL/UL128-131 expression in fibroblasts did not produce interference, suggesting a different mechanism for entry. Here, we show that the coexpression of another HCMV glycoprotein, gO, with gH/gL in human fibroblasts interferes with HCMV entry into fibroblasts but not epithelial cells. However, the coexpression of gO with gH/gL did not increase the cell surface expression level of gH/gL and did not enhance cell-cell fusion, a process that depends upon cell surface gH/gL. Instead, gO promoted the export of gH/gL from the endoplasmic reticulum (ER) and the accumulation of gH/gL in the
trans
-Golgi network. Thus, interference with gH/gL or gH/gL/gO, i.e., the mislocalization or blocking of entry mediators, occurs in cytoplasmic membranes and not in cell surface membranes of fibroblasts. Together, the results provide additional support for our hypotheses that epithelial cells express putative gH/gL/UL128-1331 receptors important for HCMV entry and that fibroblasts express distinct gH/gL receptors.
The British pig health schemes: integrated systems for large‐scale pig abattoir lesion monitoring
Authors: Sanchez‐Vazquez M. J. , Strachan W. D. , Armstrong D. , Nielen M. , Gunn G. J.
Published: September 2011

Pig health schemes based on abattoir inspections provide an integrated system to optimise the postmortem detection and the reporting of pathological lesions. In Great Britain, two initiatives have been implemented by the pig industry: Wholesome Pigs Scotland (WPS) and the BPEX Pig Health Scheme (BPHS). These schemes record the presence of a range of pathological lesions detected by means of detailed inspection of the pluck and the skin of the slaughtered pigs. The lesions are those associated with a reduction in performance traits or are indicators of animal welfare problems. This paper aims to provide an overview of the objectives behind the BPHS and their activities, outlining similarities and differences between WPS and BPHS on five main operational topics: the lesions monitored, the administration of the schemes, flow of the information, inspection strategies and the major idiosyncratic characteristics of the schemes. These initiatives inform individual producers and their veterinarians of the occurrence of pathological conditions affecting their pig herds. Additionally, they offer the added value of providing nationwide disease monitoring information and have the potential to be a useful surveillance tool for emerging and enzootic conditions.
Introgressive hybridization betweenBrahea dulcisandBrahea nitida(Arecaceae) in Mexico: evidence from morphological and PCR–RAPD patterns
Authors: Ramírez-Rodríguez R. , Tovar-Sánchez E. , Jiménez Ramírez J. , Vega Flores K. , Rodríguez V.
Published: September 2011

Gene introgression usually results from spontaneous hybridization among closely related species in sympatric populations. This phenomenon has recently become a frequent topic of interest in evolutionary and conservation biology. A palm species complex occurring in Mexico formed by two native species, Brahea dulcis (Kunth) C. Martius and Brahea nitida André, and their putative hybrids, was analyzed with morphological and molecular markers in four hybrid zones and two pure sites for each parental species. Our results showed that the closeness of the hybrids to an allopatric site of either parental species (B. nitida, mesic habitat, and B. dulcis, xeric habitat) is directly related to their morphological and genetic similarity. Also, B. dulcis differed significantly from B. nitida in all the examined characters. Morphological and molecular data were highly coincident and supported the hypothesized hybridization. Hybrid phenotypes were morphologically parent-like for 46.4% of traits, intermediate for 33.2% of traits, and transgressive for 10.0% of traits. Thus, individual hybrids appear to be a mosaic of parent-like, intermediate, and transgressive phenotypes. Our results suggest that B. nitida has been genetically assimilated by B. dulcis in Xochiapala, and in the remaining hybrid zones a unidirectional pattern of gene flow towards B. nitida exists. Therefore, hybridization may threaten the conservation status of species through genetic assimilation and may confound the ability to distinguish among taxa.
Population characteristics of old forest associated epiphytic lichens in Picea abies plantations in the boreal rainforest of Central Norway
Authors: Hilmo Olga , Ely-Aastrup Hilde , Hytteborn Håkan , Holien Håkon
Published: September 2011

The boreal rainforest in Central Norway is rich in rare and (or) red-listed epiphytic lichens but is subject to forest harvesting. Natural old Picea abies (L.) H. Karst. forests have been replaced increasingly by dense, even-aged plantations. This study aims at increasing our knowledge about populations of old forest associated lichens in P. abies plantations. In differently aged plantations, we measured occurrence of six lichen species and the population size and reproductive effort of five lichen species. We found that the success of colonizing plantations differed because of species-specific constraints and needs, and that species occurrence depended on stand age and branch quality. A high number of reproducing thalli and small juvenile thalli of the cyanolichen Lobaria scrobiculata (Scop.) DC. and the pendulous lichen Ramalina thrausta (Ach.) Nyl. suggest effective recruitment within plantations. The populations of the cyanolichens Lobaria pulmonaria (L.) Hoffm. and Pseudocyphellaria crocata (L.) Vain. were too small to be viable and demand special concern to survive in managed forests. The abundance of old forest associated lichens in a managed boreal rainforest could be promoted by a varied and heterogeneous branch structure, increased rotation periods (increase the value of plantations as propagule sources), small clearcuts and retention trees (shorten the distance between sources of propagules and target substrate), and maintaining Salix and Sorbus trees (important host trees for cyanolichens and thereby important dispersal sources).
TM4SF10 and ADAP interaction in podocytes: role in Fyn activity and nephrin phosphorylation
Authors: Azhibekov Timur A. , Wu Zhenzhen , Padiyar Aparna , Bruggeman Leslie A. , Simske Jeffrey S.
Published: September 2011

TM4SF10 [transmembrane tetra( 4 )-span family 10] is a claudin-like cell junction protein that is transiently expressed during podocyte development where its expression is downregulated in differentiating podocytes coincident with the appearance of nephrin at the slit diaphragm. In a yeast two-hybrid screen, we identified adhesion and degranulation-promoting adaptor protein (ADAP), a well-known Fyn substrate and Fyn binding partner, as a TM4SF10 interacting protein in mouse kidney. Using coimmunoprecipitation and immunohistochemistry experiments in cultured human podocytes, we show that TM4SF10 colocalizes with Fyn and ADAP but does not form a stable complex with Fyn. Cytoskeletal changes and phosphorylation events mediated by Fyn activity were reversed by TM4SF10 overexpression, including a decrease in the activating tyrosine phosphorylation of Fyn (Y421), suggesting TM4SF10 may have a regulatory role in suppressing Fyn activity. In addition, TM4SF10 was reexpressed following podocyte injury by puromycin aminonucleoside treatment, and its expression enhanced the abundance of high-molecular-weight forms of nephrin indicating it may participate in a mechanism controlling nephrin's appearance at the plasma membrane. Therefore, these studies have identified ADAP as another Fyn adapter protein expressed in podocytes, and that TM4SF10, possibly through ADAP, may regulate Fyn activity. Since TM4SF10 expression is temporally regulated during kidney development, these studies may help define a mechanism by which the slit diaphragm matures as a highly specialized cell junction during podocyte differentiation.
Identification and apical membrane localization of an electrogenic Na+/Ca2+exchanger NCX2a likely to be involved in renal Ca2+excretion by seawater fish
Authors: Islam Zinia , Kato Akira , Romero Michael F. , Hirose Shigehisa
Published: September 2011

Seawater (SW) contains ∼10 mM Ca2+, yet marine fish must drink seawater as their major water source. Thus marine teleosts fish need to excrete Ca2+to maintain whole body Ca2+homeostasis. In the intestine, seawater Ca2+interreacts with epithelial-secreted HCO3−by the intestinal epithelium, and the resulting CaCO3precipitates, which is rectally excreted. Recently the transporters involved in intestinal HCO3−secretion were identified. Ca2+is also excreted by the kidney, but the protein(s) involved in renal Ca2+excretion have not been identified. Here we identified a candidate transporter by using SW pufferfish torafugu ( Takifugu rubripes ) and its closely related euryhaline species mefugu ( Takifugu obscurus ), which are becoming useful animal models for studying molecular mechanisms of seawater adaptation. RT-PCR analyses of Na+/Ca2+exchanger (NCX) family members in various torafugu tissues demonstrated that only NCX2a is highly expressed in the kidney. Renal expression of NCX2a was markedly elevated when mefugu were transferred from freshwater to seawater. In situ hybridization and immunohistochemical analyses indicated that NCX2a is expressed in the proximal tubule at the apical membrane. NCX2a, expressed in Xenopus oocytes, conferred [Ca2+]out- and Na+-dependent currents. These results suggest that NCX2a mediates renal Ca2+secretion at the apical membrane of renal proximal tubules and has an important role in whole body Ca2+homeostasis of marine teleosts.
Muscle protein metabolism responds similarly to exogenous amino acids in healthy younger and older adults during NO-induced hyperemia
Authors: Dillon E. Lichar , Casperson Shanon L. , Durham William J. , Randolph Kathleen M. , Urban Randall J. , Volpi Elena , Ahmad Masood , Kinsky Michael P. , Sheffield-Moore Melinda
Published: September 2011

The combination of increasing blood flow and amino acid (AA) availability provides an anabolic stimulus to the skeletal muscle of healthy young adults by optimizing both AA delivery and utilization. However, aging is associated with a blunted response to anabolic stimuli and may involve impairments in endothelial function. We investigated whether age-related differences exist in the muscle protein anabolic response to AAs between younger (30 ± 2 yr) and older (67 ± 2 yr) adults when macrovascular and microvascular leg blood flow were similarly increased with the nitric oxide (NO) donor, sodium nitroprusside (SNP). Regardless of age, SNP+AA induced similar increases above baseline ( P ≤ 0.05) in macrovascular flow (4.3 vs. 4.4 ml·min−1·100 ml leg−1 measured using indocyanine green dye dilution), microvascular flow (1.4 vs. 0.8 video intensity/s measured using contrast-enhanced ultrasound), phenylalanine net balance (59 vs. 68 nmol·min−1·100 ml·leg−1), fractional synthetic rate (0.02 vs. 0.02%/h), and model-derived muscle protein synthesis (62 vs. 49 nmol·min−1·100 ml·leg−1) in both younger vs. older individuals, respectively. Provision of AAs during NO-induced local skeletal muscle hyperemia stimulates skeletal muscle protein metabolism in older adults to a similar extent as in younger adults. Our results suggest that the aging vasculature is responsive to exogenous NO and that there is no age-related difference per se in AA-induced anabolism under such hyperemic conditions.
The co-occurrence of multisensory facilitation and cross-modal conflict in the human brain
Authors: Diaconescu Andreea Oliviana , Alain Claude , McIntosh Anthony Randal
Published: September 2011

Perceptual objects often comprise a visual and auditory signature that arrives simultaneously through distinct sensory channels, and cross-modal features are linked by virtue of being attributed to a specific object. Continued exposure to cross-modal events sets up expectations about what a given object most likely “sounds” like, and vice versa, thereby facilitating object detection and recognition. The binding of familiar auditory and visual signatures is referred to as semantic, multisensory integration. Whereas integration of semantically related cross-modal features is behaviorally advantageous, situations of sensory dominance of one modality at the expense of another impair performance. In the present study, magnetoencephalography recordings of semantically related cross-modal and unimodal stimuli captured the spatiotemporal patterns underlying multisensory processing at multiple stages. At early stages, 100 ms after stimulus onset, posterior parietal brain regions responded preferentially to cross-modal stimuli irrespective of task instructions or the degree of semantic relatedness between the auditory and visual components. As participants were required to classify cross-modal stimuli into semantic categories, activity in superior temporal and posterior cingulate cortices increased between 200 and 400 ms. As task instructions changed to incorporate cross-modal conflict, a process whereby auditory and visual components of cross-modal stimuli were compared to estimate their degree of congruence, multisensory processes were captured in parahippocampal, dorsomedial, and orbitofrontal cortices 100 and 400 ms after stimulus onset. Our results suggest that multisensory facilitation is associated with posterior parietal activity as early as 100 ms after stimulus onset. However, as participants are required to evaluate cross-modal stimuli based on their semantic category or their degree of congruence, multisensory processes extend in cingulate, temporal, and prefrontal cortices.
Tissue Factor–Activated Coagulation Cascade in the Tumor Microenvironment Is Critical for Tumor Progression and an Effective Target for Therapy
Authors: Liu Yuan , Jiang Pengfei , Capkova Katerina , Xue Dong , Ye Longwu , Sinha Subhash C. , Mackman Nigel , Janda Kim D. , Liu Cheng
Published: September 2011

Tissue factor (TF), a rate-limiting enzyme cofactor in activating coagulation, is highly expressed in a wide spectrum of human tumor and tumor stromal cells. Using TF-deficient cancer cells and a conditional TF-knockout mouse model, we show that TF expressed by cancer cells, but not by the host stromal cells, plays a critical role in tumor growth. In the tumor microenvironment, serum coagulation factors are readily extravasated and therefore lead to continuous TF-mediated activation of coagulation proteases. To target this highly specific cascade of serine proteases, we used both a TF:VIIa inhibitor and doxorubicin-based prodrugs that are selectively activated by TF:FVIIa, FXa, and thrombin. Treatment with the TF:FVIIa inhibitor led to growth retardation in breast tumor models. In contrast, treatment with the prodrug eliminated primary tumor cells and lung metastases without apparent toxicity. Our findings offer preclinical proof of principle that targeting the coagulation cascade that is activated in the tumor microenvironment can be a highly effective approach for cancer therapy. Cancer Res; 71(20); 6492–502. ©2011 AACR.
EGFR- and VEGF(R)-Targeted Small Molecules Show Synergistic Activity in Colorectal Cancer Models Refractory to Combinations of Monoclonal Antibodies
Authors: Poindessous Virginie , Ouaret Djamila , El Ouadrani Karima , Battistella Aude , Mégalophonos Virginie F. , Kamsu-Kom Nyam , Petitprez Amélie , Escargueil Alexandre E. , Boudou Pascaline , Dumont Sylvie , Cervera Pascale , Fléjou Jean-François , André Thierry , Tournigand Christophe , Chibaudel Benoist , de Gramont Aimery , Larsen Annette K.
Published: September 2011

Purpose: Epidermal growth factor receptor (EGFR) and VEGF(R) signaling show extensive cross-talk, providing a rationale for joint targeting of the two pathways. However, combinations of monoclonal antibodies (mAb) targeting EGFR and VEGF showed disappointing activity in patients with colorectal cancer (CRC). We speculated that inhibition of surface receptors and ligands might only partly prevent oncogenic signaling whereas small-molecule tyrosine kinase inhibitors (TKI) would also influence intracellular signaling.

Experimental Design: Mice with CRC xenografts were treated with two TKIs, vargatef and afatinib, or with two mAbs, bevacizumab and cetuximab, and their influence on tumor growth, viability, in vivo DNA synthesis, and the presence of phosphorylated EGFR and VEGFR was determined. The activity of the TKIs was further characterized in CRC cells with different KRAS status.

Results: Vargatef and afatinib together showed strong tumor growth inhibition toward HT-29 xenografts compared with either drug alone, which was associated with a 5-fold increase in apoptotic tumor cell death. In comparison, bevacizumab and cetuximab together were exclusively cytostatic with no more activity than either drug alone. Exposure to the two TKIs was accompanied by a marked decrease of tumor-associated intracellular phospho-VEGFR1 and phospho-EGFR, whereas similar exposure to the two mAbs had no detectable effect. A synergistic activity of vargatef plus afatinib was observed in all eight CRC cell lines examined, independent of KRAS status.

Conclusions: Our results indicate that attenuation of intracellular EGFR and/or VEGF signaling is required for cytotoxic activity. These findings provide a rationale for trials of the TKIs, even in patients with mutant KRAS. Clin Cancer Res; 17(20); 6522–30. ©2011 AACR.
Prenatal Bystander Stress Alters Brain, Behavior, and the Epigenome of Developing Rat Offspring
Authors: Mychasiuk Richelle , Schmold Nichole , Ilnytskyy Slava , Kovalchuk Olga , Kolb Bryan , Gibb Robbin
Published: September 2011

The prenatal environment, including prenatal stress, has been extensively studied in laboratory animals and humans. However, studies of the prenatal environment usually directly stress pregnant females, but stress may come ‘indirectly’, through stress to a cage-mate. The current study used indirect prenatal bystander stress and investigated the effects on the gross morphology, pre-weaning behavior, and epigenome of rat offspring. Pregnant Long-Evans rats were housed with another female rat that underwent elevated platform stress from gestational days 12 to 16. We found that ultrasonic vocalizations of female cage-mates were disrupted following the stress procedure. After birth, offspring were tested on two behavioral tasks and sacrificed at postnatal day 21 (p21). Frontal cortex and hippocampal tissue was used to measure global DNA methylation and gene expression changes. At p21, bystander-stressed female offspring exhibited increased body weight. Offspring behavior on the negative geotaxis task was altered by prenatal bystander stress, and locomotor behavior was reduced in female offspring. Global DNA methylation increased in the frontal cortex and hippocampus of bystander-stressed offspring. Microarray analysis revealed significant gene expression level changes in 558 different genes, of which only 10 exhibited overlap between males and females or brain areas. These alterations in gene expression were associated with overrepresentation of 36 biological processes and 34 canonical pathways. Prenatal stress thus does not have to be experienced by the mother herself to influence offspring brain development. Furthermore, this type of ‘indirect’ prenatal stress alters offspring DNA methylation patterns, gene expression profiles, and behavior.
Early Mechanisms of Glucose Improvement following Laparoscopic Ileal Interposition Associated with a Sleeve Gastrectomy Evaluated by the Euglycemic Hyperinsulinemic Clamp in Type 2 Diabetic Patients with BMI below 35
Authors: Vencio Sergio , Stival Alessandro , Halpern Alfredo , DePaula Carolina C.L. , DePaula Aureo L.
Published: September 2011

Background: Laparoscopic ileal interposition associated with a sleeve gastrectomy (LII-SG) is a safe and effective operation for the treatment of type 2 diabetic (T2DM) patients with BMI below 35. The aim of this study was to evaluate insulin sensitivity (IS) and β-cell function using the euglycemic hyperinsulinemic clamp (EHC) with the intravenous glucose tolerance test (IVGTT). Methods: This was a prospective study of 24 T2DM patients submitted to a 3-hour EHC-IVGTT before and 1 month after LII-SG. Mean BMI was 29.0, mean age was 54.8 years and mean duration of T2DM was 10.2 years; insulin therapy was used by 62.5% of the patients. Results: Mean BMI decreased from 29.0 to 25.8 (p < 0.001). Mean fasting plasma glucose and mean postprandial glucose were 202 and 251.3 mg/dl and dropped to 127.7 and 131.8 mg/dl (p < 0.001), respectively. Mean preoperative IS was 1.4 mmol·min–1·nmol–1 and increased to 2.2 mmol· min–1·nmol–1 postoperatively (p < 0.001). Mean C-peptide AUC was 488 pmol·nmol–1 and increased to 777 pmol· nmol–1 (p = 0.37). The disposition index increased from 9.4 to 36.4 postoperatively (p = 0.01). Conclusions: According to the clamp technique, II-SG significantly improved IS and β-cell function as early as 30 days postoperatively in a T2DM population with a BMI of 21.9–33.8.
Tremor in School-Aged Children: A Cross-Sectional Study of Tremor in 819 Boys and Girls in Burgos, Spain
Authors: Louis Elan D. , Cubo Esther , Trejo-Gabriel-Galán José M. , Villaverde Vanesa Ausín , Benito Vanesa Delgado , Velasco Sara Sáez , Vicente Jesús Macarrón , Guevara José Cordero , Benito-León Julián
Published: September 2011

Background: Mild hand tremor occurs in most normal adults. There are no surveys of the prevalence or clinical correlates of such tremor among children. Methods: A cross-sectional study of tics, tremor and other neurological disorders was conducted in Spanish children; thus, 819 schoolchildren in Burgos, Spain, drew Archimedes spirals with each hand. Tremor in spirals was rated (0–2) by a blinded neurologist and an overall tremor rating (0–4) was assigned. Results: The mean age was 10.9 ± 3.1 years. A tremor rating of 1 (mild tremor) was present in either hand in 424 (51.7%) children, and in both hands in 88 (10.7%) children. Higher tremor ratings were very uncommon. The overall tremor rating was higher in boys than girls (1.31 ± 0.41 vs. 1.22 ± 0.34, p = 0.002) and correlated weakly yet significantly with age (ρ = 0.09, p = 0.01). Within subjects, the left hand spiral rating was greater than the right (p < 0.001). Conclusions: In this cross-sectional study of 819 Spanish schoolchildren, mild tremor was commonly observed. As in adults, males had more tremor than females, tremor scores increased with age, and tremor scores were higher in the left than right arm, demonstrating that these clinical correlations seem to be more broadly generalizable to children. The functional significance of tremor in children, particularly as it relates to handwriting proficiency, deserves additional scrutiny.
Plasma Viscosity in Giant Cell Arteritis
Authors: Finke Carsten , Schroeter Jan , Kalus Ulrich , Ploner Christoph J.
Published: September 2011

Background: Diagnosis of giant cell arteritis (GCA) is based on criteria of the American College of Rheumatology. However, not all GCA patients meet these criteria and treatment may be delayed in individual patients, leading to an increased risk of complications. Methods: In an observational study, we investigated acute phase response markers in GCA and non-GCA patients matched for erythrocyte sedimentation rate and CRP levels. Results: Plasma viscosity (PV) was significantly elevated in all GCA patients, but normal in non-GCA patients. Conclusions: Our data suggest that PV may reflect a more specific component of the acute inflammatory response in patients with GCA. Analysis of PV may significantly contribute to a reliable diagnosis early in the course of the disease, particularly in patients with suspected GCA that do not meet current diagnostic criteria.
Protein Interaction-Based Genome-Wide Analysis of Incident Coronary Heart Disease
Authors: Jensen Majken K. , Pers Tune H. , Dworzynski Piotr , Girman Cynthia J. , Brunak Søren , Rimm Eric B.
Published: September 2011

Background—

Network-based approaches may leverage genome-wide association (GWA) analysis by testing for the aggregate association across several pathway members. We aimed to examine if networks of genes that represent experimentally determined protein-protein interactions (PPIs) are enriched in genes associated with risk of coronary heart disease (CHD).

Methods and Results—

Genome-wide association analyses of approximately ≈700 000 single-nucleotide polymorphisms in 899 incident CHD cases and 1823 age- and sex-matched controls within the Nurses' Health and the Health Professionals Follow-up Studies were used to assign genewise
P
values. A large database of PPIs was used to assemble 8351 unbiased protein complexes and corresponding gene sets. Superimposed genewise
P
values were used to rank gene sets based on their enrichment in genes associated with CHD. After correcting for the number of complexes tested, 1 gene set was overrepresented in CHD-associated genes (
P
=0.002). Centered on the β1-adrenergic receptor gene (
ADRB1
), this complex included 18 protein interaction partners that have not been identified as candidate loci for CHD. Of the 19 genes in the top complex, 5 are involved in abnormal cardiovascular system physiological features based on knockout mice (4-fold enrichment; Fisher exact test,
P
=0.006). Ingenuity pathway analysis revealed that canonical pathways, especially related to blood pressure regulation, were significantly enriched in the genes from the top complex.

Conclusions—

The integration of a GWA study with PPI data successfully identifies a set of candidate susceptibility genes for incident CHD that would have been missed in single-marker GWA analysis.
Influence of the Anticyclonic Anomaly in the Subtropical Jet over the Western Tibetan Plateau on the Intraseasonal Variability of the Summer Asian Monsoon in Early Summer
Authors: Watanabe Takeshi , Yamazaki Koji
Published: September 2011

The upper-level troposphere over the western Tibetan Plateau, where the subtropical jet is located in summer, is a region of marked intraseasonal variability in geopotential height (GPH). This study investigates the influence of an anomaly in this region on the summer Asian monsoon. To this end, the GPH index is defined as the daily geopotential height anomaly at 200 hPa over the region based on 40-yr European Centre for Medium-Range Weather Forecasts Re-Analysis (ERA-40) data. Composites with respect to strongly positive values of the GPH index are analyzed.

The results indicate that the temporary anomaly in the subtropical jet influences the monsoon over South Asia, Southeast Asia, and probably also over East Asia, because of two main processes: the eastward propagation of quasi-stationary Rossby wave anomalies at upper and lower levels along the subtropical jet, and a belt of strong westerlies at 15°N (Arabian Sea–Bay of Bengal–the Philippines).

The two mechanisms that underlie the lower-level Rossby wave anomaly are discussed here for the first time, based on the Rossby ray-path theory, as follows: 1) anomalous descent generated by the upper-level anticyclonic anomaly over Afghanistan and the western Tibetan Plateau causes the development of a heat low over the Thar Desert and neighboring areas, and 2) an anomalous southwesterly appears over the Arabian Sea, accompanied by the heat low, and interacts with the Western Ghats, resulting in an anticyclonic anomaly over the Indian subcontinent. The anomaly then starts to propagate eastward along a Rossby waveguide.
Issues Involved in the Process of Developing a Medical Food
Authors: Ochoa Juan B. , McClave Stephen A. , Saavedra Jose
Published: September 2011

The creation of a medical food with potential health benefits for a particular patient population is a surprisingly complex process. Fortunately, the developmental process for a specific medical food is not as rigorous or as tightly regulated as that of a pharmaceutical agent. However, numerous factors unique to the enteral formulation of a new product come into play, such as physical/chemical compatibility, pH, stability, bioavailability, decay, and even palatability. Additional considerations such as strength of health benefit claims, packaging or presentation, and marketability determine the ultimate commercialization and whether a product ends up being released to the public. A full understanding of the development, substantiation, and commercialization of a medical food is necessary for important physiologic concepts in nutrition therapy to end up as part of the therapeutic regimen at the bedside of the critically ill obese patient.