bluuebunny/crossref_metadata_2025 huggingface dataset:
iGWAS: Integrative Genome‐Wide Association Studies of Genetic and Genomic Data for Disease Susceptibility Using Mediation Analysis
Authors: Huang Yen‐Tsung , Liang Liming , Moffatt Miriam F. , Cookson William O. C. M. , Lin Xihong
Published: May 2015

Genome‐wide association studies (GWAS) have been a standard practice in identifying single nucleotide polymorphisms (SNPs) for disease susceptibility. We propose a new approach, termed integrative GWAS (iGWAS) that exploits the information of gene expressions to investigate the mechanisms of the association of SNPs with a disease phenotype, and to incorporate the family‐based design for genetic association studies. Specifically, the relations among SNPs, gene expression, and disease are modeled within the mediation analysis framework, which allows us to disentangle the genetic effect on a disease phenotype into two parts: an effect mediated through a gene expression (mediation effect, ME) and an effect through other biological mechanisms or environment‐mediated mechanisms (alternative effect, AE). We develop omnibus tests for the ME and AE that are robust to underlying true disease models. Numerical studies show that the iGWAS approach is able to facilitate discovering genetic association mechanisms, and outperforms the SNP‐only method for testing genetic associations. We conduct a family‐based iGWAS of childhood asthma that integrates genetic and genomic data. The iGWAS approach identifies six novel susceptibility genes (MANEA,MRPL53,LYCAT,ST8SIA4,NDFIP1, andPTCH1) using the omnibus test with false discovery rate less than 1%, whereas no gene using SNP‐only analyses survives with the same cut‐off. The iGWAS analyses further characterize that genetic effects of these genes are mostly mediated through their gene expressions. In summary, the iGWAS approach provides a new analytic framework to investigate the mechanism of genetic etiology, and identifies novel susceptibility genes of childhood asthma that were biologically meaningful.
Late Triassic aetosaur (Archosauria) from Krasiejów (SW Poland): new species or an example of individual variation?
Authors: Antczak Mateusz
Published: May 2015

An aetosaur discovery in Krasiejów (SW Poland), in Late Triassic deposits, was first described by Sulej in 2010 as a new species carrying the name Stagonolepis olenkae. However, new fossil material suggests that its taxonomical position is not as clear as was initially presumed. In the new material from the ‘Triassic’ site of Krasiejów, the typical features of Stagonolepis robertsoni, described by Walker in 1961 from the Elgin area of Scotland, were identified (i.e. frontal/prefrontal width ratio), as well as features of S. olenkae (i.e. angle between ventral edge of the maxilla and ventral edge of the antorbital fenestra). However, distinct features from both species, such as the shape of the canal at the dorsal surface of the frontal, are present. Some of the variation is similar to sexual dimorphism observed in recent amphibians and reptiles. These variations, as well as the fact that the postcranial skeleton was previously described as S. robertsoni by Lucas and co‐workers in 2007, suggest that the taxonomical affiliation of the Krasiejów aetosaur (and/or the number of aetosaur species) should be re‐considered. Copyright © 2015 John Wiley & Sons, Ltd.
Phosphorylation of the nuclear receptor corepressor 1 by protein kinase B switches its corepressor targets in the liver in mice
Authors: Jo Young Suk , Ryu Dongryeol , Maida Adriano , Wang Xu , Evans Ronald M. , Schoonjans Kristina , Auwerx Johan
Published: May 2015

Nuclear receptor corepressor 1 (NCoR1) is a transcriptional coregulator that has wide‐ranging effects on gene expression patterns. In the liver, NCoR1 represses lipid synthesis in the fasting state, whereas it inhibits activation of peroxisome proliferator‐activated receptor alpha (PPARα) upon feeding, thereby blunting ketogenesis. Here, we show that insulin by activation of protein kinase B induces phosphorylation of NCoR1 on serine 1460, which selectively favors its interaction with PPARα and estrogen‐related receptor alpha (ERRα) over liver X receptor alpha (LXRα). Phosphorylation of NCoR1 on S1460 selectively derepresses LXRα target genes, resulting in increased lipogenesis, whereas, at the same time, it inhibits PPARα and ERRα targets, thereby attenuating oxidative metabolism in the liver. Phosphorylation‐gated differential recruitment of NCoR1 to different nuclear receptors explains the apparent paradox that liver‐specific deletion of NCoR1 concurrently induces both lipogenesis and oxidative metabolism owing to a global derepression of LXRα, PPARα, and ERRα activity. Conclusion: Phosphorylation‐mediated recruitment switch of NCoR1 between nuclear receptor subsets provides a mechanism by which corepressors can selectively modulate liver energy metabolism during the fasting‐feeding transition. (Hepatology 2015;62:1606–1618)
Interferon‐inducible cholesterol‐25‐hydroxylase restricts hepatitis C virus replication through blockage of membranous web formation
Authors: Anggakusuma  , Romero‐Brey Inés , Berger Carola , Colpitts Che C. , Boldanova Tujana , Engelmann Michael , Todt Daniel , Perin Paula Monteiro , Behrendt Patrick , Vondran Florian W.R. , Xu Shuting , Goffinet Christine , Schang Luis M. , Heim Markus H. , Bartenschlager Ralf , Pietschmann Thomas , Steinmann Eike
Published: May 2015

Hepatitis C virus (HCV) is a positive‐strand RNA virus that primarily infects human hepatocytes. Infections with HCV constitute a global health problem, with 180 million people currently chronically infected. Recent studies have reported that cholesterol 25‐hydroxylase (CH25H) is expressed as an interferon‐stimulated gene and mediates antiviral activities against different enveloped viruses through the production of 25‐hydroxycholesterol (25HC). However, the intrinsic regulation of human CH25H (hCH25H) expression within the liver as well as its mechanistic effects on HCV infectivity remain elusive. In this study, we characterized the expression of hCH25H using liver biopsies and primary human hepatocytes. In addition, the antiviral properties of this protein and its enzymatic product, 25HC, were further characterized against HCV in tissue culture. Levels of hCH25H messenger RNA were significantly up‐regulated both in HCV‐positive liver biopsies and in HCV‐infected primary human hepatocytes. The expression of hCH25H in primary human hepatocytes was primarily and transiently induced by type I interferon. Transient expression of hCH25H in human hepatoma cells restricted HCV infection in a genotype‐independent manner. This inhibition required the enzymatic activity of CH25H. We observed an inhibition of viral membrane fusion during the entry process by 25HC, which was not due to a virucidal effect. Yet the primary effect by 25HC on HCV was at the level of RNA replication, which was observed using subgenomic replicons of two different genotypes. Further analysis using electron microscopy revealed that 25HC inhibited formation of the membranous web, the HCV replication factory, independent of RNA replication. Conclusion: Infection with HCV causes up‐regulation of interferon‐inducible CH25H in vivo, and its product, 25HC, restricts HCV primarily at the level of RNA replication by preventing formation of the viral replication factory. (Hepatology 2015;62:702–714)
Involvement of a cyclic adenosine monophosphate–dependent signal in the diet‐induced canalicular trafficking of adenosine triphosphate–binding cassette transporter g5/g8
Authors: Yamazaki Yasuhiro , Yasui Kenta , Hashizume Takahiro , Suto Arisa , Mori Ayaka , Murata Yuzuki , Yamaguchi Masahiko , Ikari Akira , Sugatani Junko
Published: May 2015

The adenosine triphosphate–binding cassette (ABC) half‐transporters Abcg5 and Abcg8 promote the secretion of neutral sterol into bile. Studies have demonstrated the diet‐induced gene expression of these transporters, but the regulation of their trafficking when the nutritional status changes in the liver remains to be elucidated. Here, we generated a novel in vivo kinetic analysis that can monitor the intracellular trafficking of Abcg5/Abcg8 in living mouse liver by in vivo transfection of the genes of fluorescent protein‐tagged transporters and investigated how hypernutrition affects the canalicular trafficking of these transporters. The kinetic analysis showed that lithogenic diet consumption accelerated the translocation of newly synthesized fluorescent‐tagged transporters to intracellular pools in an endosomal compartment and enhanced the recruitment of these pooled gene products into the bile canalicular membrane in mouse liver. Because some ABC transporters are reported to be recruited from intracellular pools to the bile canaliculi by cyclic adenosine monophosphate (cAMP) signaling, we next evaluated the involvement of this machinery in a diet‐induced event. Administration of a protein kinase A inhibitor, N‐(2‐{[3‐(4‐bromophenyl)−2‐propenyl]amino}ethyl)−5‐isoquinolinesulfonamide, decreased the canalicular expression of native Abcg5/Abcg8 in lithogenic diet–fed mice, and injection of a cAMP analog, dibutyryl cAMP, transiently increased their levels in standard diet–fed mice, indicating the involvement of cAMP signaling. Indeed, canalicular trafficking of the fluorescent‐tagged Abcg5/Abcg8 was enhanced by dibutyryl cAMP administration. Conclusion: These observations suggest that diet‐induced lipid loading into liver accelerates the trafficking of Abcg5/Abcg8 to the bile canalicular membrane through cAMP signaling machinery. (Hepatology 2015;62:1215‐1226)
Reproducibility of mRECIST in assessing response to transarterial radioembolization therapy in hepatocellular carcinoma
Authors: Seyal Adeel R. , Gonzalez‐Guindalini Fernanda D. , Arslanoglu Atilla , Harmath Carla B. , Lewandowski Robert J. , Salem Riad , Yaghmai Vahid
Published: May 2015

The purpose of our study was to evaluate the reproducibility of Modified Response Evaluation Criteria in Solid Tumors (mRECIST) in hepatocellular carcinoma (HCC) lesions undergoing transarterial radioembolization (TARE) therapy and to determine whether mRECIST reproducibility is affected by the enhancement pattern of HCC. One hundred and three HCC lesions from 103 patients treated with TARE were evaluated. The single longest diameter of viable tumor tissue was measured by two radiologists at baseline; response to therapy was evaluated according to mRECIST. The enhancement pattern of HCC lesions was correlated with their mRECIST response. The response rate between mRECIST and RECIST 1.1 was compared. Wilcoxon signed‐rank test, paired t test, Lin's concordance correlation coefficient (ρ
c), Bland‐Altman plot, kappa statistics, and Fisher's exact test were used to assess intra‐ and interobserver reproducibilities and to compare response rates. There were better intra‐ than interobserver agreements in the measurement of single longest diameter of viable tumor tissue (bias = 0 cm intraobserver versus bias = 0.3 cm interobserver). For mRECIST, good intraobserver (ĸ = 0.70) and moderate interobserver (ĸ = 0.56) agreements were noted. The mRECIST response for HCC lesions with homogeneous enhancement at both baseline and follow‐up imaging showed better intra‐ and interobserver agreements (ĸ = 0.77 and 0.60, respectively) than lesions with heterogeneous enhancement at both scans (ĸ = 0.54 and 0.40, respectively). In the early follow‐up period mRECIST showed a significantly higher response rate than RECIST (40.8% versus 3.9%; P = 0.025). Conclusions: In HCC patients treated with TARE, mRECIST captures a significantly higher response rate compared with RECIST; it also demonstrates acceptable intra‐ and interobserver reproducibilities for HCC lesions treated with TARE, and mRECIST reproducibility may be lower for HCC lesions with heterogeneous distribution of the viable tumor tissue. (Hepatology 2015;62:1111‐1121)
Transit time distributions, legacy contamination and variability in biogeochemical 1/fαscaling: how are hydrological response dynamics linked to water quality at the catchment scale?
Authors: Hrachowitz Markus , Fovet Ophelie , Ruiz Laurent , Savenije Hubert H. G.
Published: May 2015

In spite of recent progress, hydrological processes underlying observed water quality response patterns, such as the emergence of near‐chemostatic conditions and fractal 1/fαscaling of stream chemistry, are not completely understood. Analysing hydrological and Cl−tracer data for two intensely managed, hydrologically contrasting yet biogeochemically similar catchments we tested if (1) a semi‐distributed, conceptual model can simultaneously reproduce catchment scale hydrological and biogeochemical responses, (2) legacy stores, allowing for long‐term storage of nutrient inputs can be identified and (3) a model can reproduce 1/fαscaling. Further we analysed (4) transit (TTD) and residence time distributions (RTD) and the associated response dynamics of legacy stores, to explore (5) what controls fluctuations in the scaling exponent α, thereby establishing a process based link between 1/fαscaling, legacy stores and age distributions. We found that the model could reproduce the variable hydrological and the stable Cl−responses. This was possible through Cl−accumulation in hydrologically passive legacy stores that are mainly associated with the groundwater store, where Cl−age is well above 2000 days, one magnitude above the Cl−age in other components, such as the root zone (~200 d). The results indicate that legacy stores can cause stable nutrient concentrations in streams for several decades after the end of nutrient input. It was further found that the model could reproduce fractal scaling of stream Cl−in both catchments, with higher values of α for the catchment with the smaller legacy store and faster response (α = −0.88vs−1.29). Further analysing the spectral properties of model components, it was found that the parts of the system with less storage are characterized by higher values of α. This suggests a plausible processes‐based link between the fluctuations of α, legacy stores and RTDs: the smaller the legacy store and the higher the flow contribution from faster responding system components, the higher α, suggesting that fractal scaling may potentially not be a universally emerging property of the biogeochemical response in streams. Copyright © 2015 John Wiley & Sons, Ltd.
Further evaluation of the high‐probability instructional sequence with and without programmed reinforcement
Authors: Wilder David A. , Majdalany Lina , Sturkie Latasha , Smeltz Lindsay
Published: May 2015

In 2 experiments, we examined the effects of programmed reinforcement for compliance with high‐probability (high‐p) instructions on compliance with low‐probability (low‐p) instructions. In Experiment 1, we compared the high‐p sequence with and without programmed reinforcement (i.e., edible items) for compliance with high‐p instructions. Results showed that the high‐p sequence increased compliance with low‐p instructions only when compliance with high‐p instructions was followed by reinforcement. In Experiment 2, we examined the role of reinforcer quality by delivering a lower quality reinforcer (praise) for compliance with high‐p instructions. Results of Experiment 2 showed that the high‐p sequence with lower quality reinforcement did not improve compliance with low‐p instructions; the addition of a higher quality reinforcer (i.e., edible items) contingent on compliance with high‐p instructions did increase compliance with low‐p instructions.
Onset of hepatocarcinogen‐specific cell proliferation and cell cycle aberration during the early stage of repeated hepatocarcinogen administration in rats
Authors: Kimura Masayuki , Abe Hajime , Mizukami Sayaka , Tanaka Takeshi , Itahashi Megu , Onda Nobuhiko , Yoshida Toshinori , Shibutani Makoto
Published: May 2015

We have previously reported that a 28‐day treatment of carcinogens evoking target cell proliferation activates G1/S checkpoint function and apoptosis, as well as induction of aberrant ubiquitin D (Ubd) expression, suggesting disruptive spindle checkpoint function, in rats. The present study aimed to determine the onset time of rat liver cells to undergo carcinogen‐specific cell cycle aberration and proliferation. Animals were treated orally with a hepatocarcinogenic dose of methyleugenol or thioacetamide for 3, 7 or 28 days. For comparison, some animals were subjected to partial hepatectomy or treated with noncarcinogenic hepatotoxicants (acetaminophen, α‐naphthyl isothiocyanate or promethazine). Carcinogen‐specific liver cell kinetics appeared at day 28 as evident by increases of cell proliferation, p21Cip1+ cells, phosphorylated‐Mdm2+ cells and cleaved caspase 3+ cells, and upregulation of DNA damage‐related genes. Hepatocarcinogens also downregulated Rbl2 and upregulated Cdkn1a and Mdm2, and decreased Ubd+ cells co‐expressing phosphorylated‐histone H3 (p‐Histone H3) and p‐Histone H3+ cell ratio within the Ki‐67+ proliferating population. These results suggest that it takes 28 days to induce hepatocarcinogen‐specific early withdrawal of proliferating cells from M phase due to disruptive spindle checkpoint function as evidenced by reduction of Ubd+ cells staying at M phase. Disruption of G1/S checkpoint function reflected by downregulation of Rbl2 as well as upregulation of Mdm2 suggestive of sequestration of retinoblastoma protein is responsible for the facilitation of carcinogen‐induced cell proliferation at day 28. Accumulation of DNA damage probably in association with facilitation of p53 degradation by activation of Mdm2 may be a prerequisite for aberrant p21Cip1 activation, which is responsible for apoptosis. Copyright © 2015 John Wiley & Sons, Ltd.
An open‐label, phase 1 study to evaluate the effects of hepatic impairment on edoxaban pharmacokinetics and pharmacodynamics
Authors: Mendell Jeanne , Johnson Lisa , Chen Shuquan
Published: May 2015

Edoxaban, a once‐daily, oral, direct factor Xa inhibitor, is approved for stroke prevention in nonvalvular atrial fibrillation and venous thromboembolism treatment. This study examined the effects of mild or moderate hepatic impairment on the pharmacokinetics of edoxaban and its metabolite M4. Thirty‐three subjects enrolled in 4 treatment cohorts—mild hepatic impairment (n = 8), moderate hepatic impairment (n = 9), and 2 cohorts of healthy controls matched for age, sex, and weight (each n = 8)—and received a single 15‐mg dose of edoxaban. Plasma pharmacokinetics for edoxaban and M4, prothrombin time (PT), activated partial thromboplastin time (aPTT), and safety data were measured over 72 hours. Edoxaban and M4 exposures were similar in subjects with mild or moderate hepatic impairment compared with matched controls. Higher PT and aPTT values were observed at baseline and after edoxaban dosing in the hepatic impairment groups compared with healthy controls. Edoxaban 15 mg was well tolerated in all cohorts. These results suggest that edoxaban exposure does not significantly increase in patients with mild or moderate hepatic impairment. However, because of the potential for underlying coagulopathy, edoxaban is not recommended for use in patients with moderate or severe hepatic impairment. No dose reduction is recommended for patients with mild hepatic impairment.
Synthesis of 68Ga‐labeled NOTA‐RGD‐GE11 heterodimeric peptide for dual integrin and epidermal growth factor receptor‐targeted tumor imaging
Authors: Yu Hung‐Man , Chen Jyun‐Hong , Lin Kun‐Liang , Lin Wuu‐Jyh
Published: May 2015

Radiolabeled Arg‐Gly‐Asp (RGD) peptide analogs have been extensively studied for αvβ3 integrin‐targeted angiogenesis imaging. According to recently presented evidence, the dodecapeptide GE11 has high affinity to the epidermal growth factor receptor (EGFR), which is overexpressed in many types of cancer. Dual‐receptor molecular imaging probes with two different heterodimeric peptides exhibit improved cancer targeting efficacy. In the present study, the design and synthesis of a new RGD‐GE11 peptide heterodimer for dual αvβ3 integrin/EGFR‐targeted cancer imaging are described. The RGD‐GE11 heterodimer was linked with 6‐aminohexanoic acid (6‐Ahx) and cysteine and conjugated with 1,4,7‐triazacyclononane‐N,N′,N″‐triacetic acid (NOTA) to form NOTA‐RGD‐cys‐6‐Ahx‐GE11. The monomeric peptides, NOTA‐cys‐6‐Ahx‐GE11 and c(RGDyK), were formed by a peptide synthesizer. The peptide heterodimer NOTA‐RGD‐GE11 was obtained by NOTA‐cys‐6‐Ahx‐GE11 and maleimidopropyl‐c(RGDyK) conjugation with a thioether linkage. The NOTA peptide conjugate was labeled with freshly eluted 68Ga and purified using reversed‐phase high‐performance liquid chromatography. The 68Ga‐NOTA‐RGD‐cys‐6‐Ahx‐GE11 was successfully prepared, in this study, with a radiochemical yield of 85% and a radiochemical purity of >98%. These results warrant further investigation of this heterodimeric peptide's binding affinity to the receptors.
Peramorphic traits in the tokay gecko skull
Authors: Daza Juan D. , Mapps Aurelia A. , Lewis Patrick J. , Thies Monte L. , Bauer Aaron M.
Published: May 2015

Traditionally, geckos have been conceived to exhibit paedomorphic features relative to other lizards (e.g., large eyes, less extensively ossified skulls, and amphicoelous and notochordal vertebrae). In contrast, peramorphosis has not been considered an important process in shaping their morphology. Here, we studied different sized specimens of Gekko gecko to document ontogenetic changes in cranial anatomy, especially near maturity. Comparison of this species with available descriptions of other geckos resulted in the identification of 14 cranial characteristics that are expressed more strongly with size increase. These characteristics become move evident in later stages of post‐hatching development, especially near maturation, and are, therefore, attributed to peramorphosis (hyperossification). ACCTRAN and DELTRAN character optimizations were applied to these characters using a tree of 11 genera derived from a gekkotan molecular phylogeny. This analysis revealed that G. gecko expresses the majority of these putative peramorphic features near maturity, and that some of these features are also expressed in species closely related to G. gecko. The characters studied have the potential to be applied in future phylogenetic and taxonomic studies of this group of lizards. J. Morphol. 276:915–928, 2015. © 2015 Wiley Periodicals, Inc.
Coproduction of detergent compatible bacterial enzymes and stain removal evaluation
Authors: Niyonzima Francois N. , More Sunil S.
Published: May 2015

Most of the detergents that are presently produced contain the detergent compatible enzymes to improve and accelerate the washing performance by removing tough stains. The process is environment friendly as the use of enzymes in the detergent formulation reduces the utilization of toxic detergent constituents. The current trend is to use the detergent compatible enzymes that are active at low and ambient temperature in order to save energy and maintain fabric quality. As the detergent compatible bacterial enzymes are used together in the detergent formulation, it is important to co‐produce the detergent enzymes in a single fermentation medium as the enzyme stability is assured, and production cost gets reduced enormously. The review reports on the production, purification, characterization and application of detergent compatible amylases, lipases, and proteases are available. However, there is no specific review or minireview on the concomitant production of detergent compatible amylases, lipases, and proteases. In this minireview, the coproduction of detergent compatible enzymes by bacterial species, enzyme stability towards detergents and detergent components, and stain release analysis were discussed.
Viral load and mRNA expression of HPV type 6 among cases with recurrent respiratory papillomatosis
Authors: Forslund Ola , Schwartz Stefan , Olofsson Katarina , Rydell Roland
Published: May 2015

Objectives/Hypothesis

To determine viral load of human papillomavirus type 6 (HPV6), physical state of HPV6‐DNA, and transcription level of HPV6 E7‐mRNA in laryngeal papilloma and in adjacent healthy mucosa.

Study Design

Case series.

Methods

A papilloma biopsy was collected from each of 25 adult patients with respiratory recurrent papillomatosis. From 14 of the 25 patients, we first collected a biopsy from healthy mucosa of the false vocal fold and another from the papilloma. Quantity of HPV6 and E7‐mRNA was measured by polymerase chain reaction.

Results

For the papilloma, the median load of HPV6 was 41 copies/cell, and the lowest amount was 5.4 copies/cell. Human papillomavirus type 6 was detected in 50% (7/14) of the healthy mucosa, with a median of 1.1 copies/cell, and the highest amount was 6.6 copies/cell. Overall, viral load was higher in papilloma than in healthy mucosa (P < 0.05). The average HPV6 E2/E7‐DNA ratio was 1.3, indicating an episomal state. Human papillomavirus type 6‐mRNA was detected in all HPV6‐DNA‐positive samples. The transcription median ratio of HPV6‐mRNA/HPV6‐DNA was 1.5 in papilloma and 3.8 in healthy mucosa.

Conclusion

The amount of HPV6‐DNA was consistently higher in the papilloma than in healthy mucosa. The transcription level of HPV6 E7 mRNA was similar in the papilloma and in normal mucosa. We suggest that interfering with replication of HPV6 and suppression of HPV6 to fewer than five copies/cell may be curative.

Level of Evidence

N/A. Laryngoscope, 126:122–127, 2016
Early spring phytoplankton dynamics in the subpolar North Atlantic: The influence of protistan herbivory
Authors: Morison Françoise , Menden‐Deuer Susanne
Published: May 2015

We measured phytoplankton‐growth (μ) and herbivorous‐protist grazing (g) rates in relation to mixed‐layer‐depth (MLD) during the March/April 2012 EuroBasin cruise in the subpolar North Atlantic. We performed 15 dilution experiments at two open‐ocean (∼ 1300 m) and one shelf (160 m) station. Of the two open‐ocean stations one was deeply mixed (476 m), the other stratified (46 m). At the shelf station, MLD reached the bottom. Initial chlorophyll a (Chl a) varied from 0.2–1.9 μg L−1 and increased up to 2.7 μg L−1 at the shelf station. In 80% of experiments, regardless of MLD, growth‐rates exceeded grazing‐mortality rates. At the open‐ocean stations, the deep ML coincided with μ and g that varied over the same range (≤ 0–0.6 d−1), whereas stratification corresponded to μ and g that ranged from 0.14–0.41 d−1 to 0.11–0.34 d−1, respectively. At the stratified station, the balance between μ and g explained 98% of in situ variations in Chl a, whereas at the deep‐ML station, rate estimates had no explanatory power. The consistent relationship between μ and g, which corresponded to a grazing‐removal of 64% of primary production, suggests that g might be predictable if μ is known, and that a coefficient of 0.64 may be a useful parameter for subarctic carbon models. Composition and persistence of the plankton assemblages differed at the stations and may have been a significant driver of grazing‐pressure. Overall, these results showed no association of MLD with grazing‐pressure and highlight the need to assess to what extent MLD represents the depth of active‐mixing to understand the effects of protistan‐grazing on the development of the North Atlantic spring bloom.
Model companions of theories of graphs
Authors: Takeuchi Kota , Tanaka Yu‐ichi , Tsuboi Akito
Published: May 2015

We study model companions of theories extending the graph axioms. First we prove general results concerning the existence of the model companion. Then, by applying these results to the case of graphs, we give a series of companionable and non‐companionable examples.
High nigral iron deposition in LRRK2 and Parkin mutation carriers using R2* relaxometry
Authors: Pyatigorskaya Nadya , Sharman Michael , Corvol Jean‐Christophe , Valabregue Romain , Yahia‐Cherif Lydia , Poupon Fabrice , Cormier‐Dequaire Florence , Siebner Hartwig , Klebe Stephan , Vidailhet Marie , Brice Alexis , Lehéricy Stephane
Published: May 2015

Objectives

The goal of this work was to investigate iron deposition in the basal ganglia and thalamus in symptomatic and asymptomatic leucine‐rich repeat kinase 2 (LRRK2) and Parkin‐associated Parkinson's disease (PD), using R2* relaxometry rate.

Methods

Twenty subjects with genetic PD (four symptomatic and two asymptomatic Parkin subjects, nine symptomatic and five asymptomatic LRRK2 subjects) were compared with 20 patients with idiopathic PD (IPD) and 20 healthy subjects. Images were obtained at 3 teslas, using multi‐echo T2 and T2* sequences. R2 and R2* values were calculated in the substantia nigra (SN), the striatum, the globus pallidus, and the thalamus.

Results

The R2* values in the SN were increased in IPD and mutation‐carrying patients as compared with controls and in mutation‐carrying patients as compared with IPD. Asymptomatic mutation carriers showed higher R2* values than controls and did not differ from IPD patients. No changes were seen in the other structures or in R2 values.

Conclusion

These results are consistent with increased iron load in LRRK2‐ and Parkin‐mutation carriers. The increased R2* in asymptomatic PD‐mutation carriers suggests that iron deposition occurs early during the preclinical phase of the disease. R2* measurements may be used as markers for investigating nigrostriatal damage in preclinical mutation‐carrying patients. © 2015 International Parkinson and Movement Disorder Society
A unique continuation result for the plate equation and an application
Authors: Arat Zehra , Khanmamedov Azer , Simsek Sema
Published: May 2015

In this paper, we prove the unique continuation property for the weak solution of the plate equation with the low regular coefficient. Then, we apply this result to study the global attractor for the semilinear plate equation with a localized damping. Copyright © 2015 John Wiley & Sons, Ltd.
MP2 calculation of 77Se NMR chemical shifts taking into account relativistic corrections
Authors: Rusakov Yury Yu. , Rusakova Irina L. , Krivdin Leonid B.
Published: May 2015

The main factors affecting the accuracy and computational cost of the Second‐order Möller‐Plesset perturbation theory (MP2) calculation of 77Se NMR chemical shifts (methods and basis sets, relativistic corrections, and solvent effects) are addressed with a special emphasis on relativistic effects. For the latter, paramagnetic contribution (390–466 ppm) dominates over diamagnetic term (192–198 ppm) resulting in a total shielding relativistic correction of about 230–260 ppm (some 15% of the total values of selenium absolute shielding constants). Diamagnetic term is practically constant, while paramagnetic contribution spans over 70–80 ppm. In the 77Se NMR chemical shifts scale, relativistic corrections are about 20–30 ppm (some 5% of the total values of selenium chemical shifts). Solvent effects evaluated within the polarizable continuum solvation model are of the same order of magnitude as relativistic corrections (about 5%). For the practical calculations of 77Se NMR chemical shifts of the medium‐sized organoselenium compounds, the most efficient computational protocols employing relativistic Dyall's basis sets and taking into account relativistic and solvent corrections are suggested. The best result is characterized by a mean absolute error of 17 ppm for the span of 77Se NMR chemical shifts reaching 2500 ppm resulting in a mean absolute percentage error of 0.7%. Copyright © 2015 John Wiley & Sons, Ltd.
Monitoring organic reactions by UF‐NMR spectroscopy
Authors: Herrera Antonio , Fernández‐Valle Encarnación , Martínez‐Álvarez Roberto , Molero‐Vílchez Dolores , Pardo‐Botero Zulay D. , Sáez‐Barajas Elena
Published: May 2015

Standard 2D NMR experiments suffer from the many t1 increments needed for spectra with sufficient digital resolution in the indirect dimension. Despite the different methodological approaches to overcome this problem, these increments have prevented studies of fast reactions. The development of ultrafast NMR (UF‐NMR) has decisively speeded up the time scale of standard NMR to allow the study of organic reactions as they happen in real time to reveal mechanistic details. This mini‐review summarizes the results achieved in monitoring organic reactions through this exciting technique. Copyright © 2015 John Wiley & Sons, Ltd.
Measuring age‐dependent myocardial stiffness across the cardiac cycle using MR elastography: A reproducibility study
Authors: Wassenaar Peter A. , Eleswarpu Chethanya N. , Schroeder Samuel A. , Mo Xiaokui , Raterman Brian D. , White Richard D. , Kolipaka Arunark
Published: May 2015

Purpose

To assess reproducibility in measuring left ventricular (LV) myocardial stiffness in volunteers throughout the cardiac cycle using MR elastography (MRE) and to determine its correlation with age.

Methods

Cardiac MRE (CMRE) was performed on 29 normal volunteers, with ages ranging from 21 to 73 years. For assessing reproducibility of CMRE‐derived stiffness measurements, scans were repeated per volunteer. Wave images were acquired throughout the LV myocardium, and were analyzed to obtain mean stiffness during the cardiac cycle. CMRE‐derived stiffness values were correlated to age.

Results

Concordance correlation coefficient revealed good interscan agreement with rc of 0.77, with P‐value < 0.0001. Significantly higher myocardial stiffness was observed during end‐systole (ES) compared with end‐diastole (ED) across all subjects. Additionally, increased deviation between ES and ED stiffness was observed with increased age.

Conclusion

CMRE‐derived stiffness is reproducible, with myocardial stiffness changing cyclically across the cardiac cycle. Stiffness is significantly higher during ES compared with ED. With age, ES myocardial stiffness increases more than ED, giving rise to an increased deviation between the two. Magn Reson Med 75:1586–1593, 2016. © 2015 Wiley Periodicals, Inc.
Elevated levels of GABA+ in migraine detected using 1H‐MRS
Authors: Aguila Maria‐Eliza R. , Lagopoulos Jim , Leaver Andrew M. , Rebbeck Trudy , Hübscher Markus , Brennan Patrick C. , Refshauge Kathryn M.
Published: May 2015

γ‐Aminobutyric acid (GABA) has been implicated in several pain conditions, yet no study has systematically evaluated GABA levels in migraine using 1H‐MRS. The accurate detection, separation and quantification of GABA in individuals with migraine could elucidate the role of this neurotransmitter in migraine pathophysiology. Such information may eventually be useful in the diagnosis and development of more effective treatments for migraine. The aims of this study were therefore to compare the concentration of GABA+ in individuals with migraine with that in asymptomatic individuals, and to determine the diagnostic potential of GABA+ in the classification of those with or without migraine. In this case–control study, GABA+ levels in the brain were determined in 19 participants with migraine and 19 matched controls by 1H‐MRS using Mescher–Garwood point‐resolved spectroscopy (MEGA‐PRESS) sequence. The diagnostic accuracy of GABA+ for the detection of migraine and the optimal cut‐off value were determined by receiver operating characteristic analysis. GABA+ levels were significantly higher (p = 0.002) in those with migraine [median, 1.41 institutional units (IU); interquartile range, 1.31–1.50 IU] than in controls (median, 1.18 IU; interquartile range, 1.12–1.35 IU). The GABA+ concentration appears to have good accuracy for the classification of individuals with or without migraine [area under the curve (95% confidence interval), 0.837 (0.71–0.96); p < 0.001]. The optimal GABA+ cut‐off value for migraine was 1.30 IU, with a sensitivity of 84.2%, specificity of 68.4% and positive likelihood ratio of +2.67. The outcomes of this study suggest altered GABA metabolism in migraine. These results add to the scarce evidence on the putative role of GABA in migraine and provide a basis to further explore the causal relationship between GABA+ and the pathophysiology of migraine. This study also demonstrates that GABA+ concentration has good diagnostic accuracy for migraine. These findings offer new research and practice directions for migraine diagnosis. Copyright © 2015 John Wiley & Sons, Ltd.
New 3D geometrical deposition methods for efficient packing of spheres based on tangency
Authors: De Cola F. , Falco S. , Barbieri E. , Petrinic N.
Published: May 2015

The morphology of many natural and man‐made materials at different length scales can be simulated using particle‐packing methods. This paper presents two novel 3D geometrical collective deposition algorithms for packed assemblies with prescribed distribution of radii: the ‘planar deposition’ and the ‘3D‐clew’ method. The ‘planar deposition’ method mimics an orderly granular flow through a funnel by stacking up spirally ordinated planar assemblies of spheres capable of achieving the theoretical maximum for monodisperse aggregates. The ‘3D‐clew’ method, instead, mimics the winding of a clew of yarn, thus yielding densely packed 3D polydispersed assemblies in terms of void ratio of the aggregate. The morphologies of such geometrically generated assemblies, achieved at several orders of magnitude reduced computational cost, are comparable with those consolidated uni‐directionally by means of discrete element method. In addition, significantly faster simulations of mechanical consolidation of granular media have been performed when relying upon the proposed geometrically generated assemblies as starting configurations. Copyright © 2015 John Wiley & Sons, Ltd.
β‐Crystal formation in isotactic polypropylene due to rapid heat cycle molding
Authors: Li Jiquan , Zhou Hangchao , Xu Fuyu , Jiang Shaofei , Zheng Wei
Published: May 2015

Performance of the rapid heat cycle‐molded products is highly correlated to its multilayer structure and crystal form in the multilayers. In this study, isotactic polypropylene was introduced in molding experiments, multi‐sites sampling was carried out, and β‐crystal contents together with multilayer structure were characterized by scanning electron microscopy and X‐ray diffraction. It is shown that the distribution of β‐crystal is significantly relevant to the multilayer structure. Meanwhile, a higher mold‐heating temperature would benefit the formation of β‐crystal, the content of which is mainly dependent on mold temperature and filling distance. Copyright © 2015 John Wiley & Sons, Ltd.
Treatment of neuroblastoma in congenital central hypoventilation syndrome with a PHOX2B polyalanine repeat expansion mutation: New twist on a neurocristopathy syndrome
Authors: Armstrong Amy E. , Weese‐Mayer Debra E. , Mian Amir , Maris John M. , Batra Vandana , Gosiengfiao Yasmin , Reichek Jennifer , Madonna Mary Beth , Bush Jonathan W. , Shore Richard M. , Walterhouse David O.
Published: May 2015

Neuroblastoma in patients with congenital central hypoventilation syndrome (CCHS) as part of a neurocristopathy syndrome is a rare finding and has only been associated with paired‐like homeobox 2b (PHOX2B) non‐polyalanine‐repeat‐expansion mutations. To the best of our knowledge, we report the first case of a child with CCHS and Hirschsprung disease who had a PHOX2B polyalanine‐repeat‐expansion mutation (PARM) (genotype 20/33) and developed high‐risk neuroblastoma. We further describe his treatment including chemotherapy and therapeutic I131‐metaiodobenzylguanidine. This case highlights the need to consider neuroblastoma in patients with CCHS and the longest PHOX2B PARMs and to individualize treatment based on co‐morbidities. Pediatr Blood Cancer © 2015 Wiley Periodicals, Inc.
Ovary preservation in the treatment of childhood Meigs syndrome
Authors: Fremed Michael A. , Levin Terry L. , Sun Katherine Y. , Weiser Daniel A.
Published: May 2015

Meigs syndrome, the combination of benign ovarian tumor, ascites, and pleural effusion, is present in a small percentage of ovarian fibromas and is infrequently reported in children. When associated with elevated CA‐125 suspicion is raised for malignancy, often prompting aggressive surgical intervention. We present a case of childhood Meigs syndrome and review the relevant literature with emphasis on ovary preservation. Out of nine identified pediatric cases, one involved ovary sparing treatment and none recurred or progressed to malignancy. Our report highlights the importance of presurgical identification of Meigs syndrome in order to curtail salpingo‐oophorectomy when feasible. Pediatr Blood Cancer © 2015 Wiley Periodicals, Inc.
Maximum power point tracker based on maximum power point resistance modeling
Authors: Enrique Juan Manuel , Andújar José Manuel , Durán Eladio , Martínez Miguel Angel
Published: May 2015

This paper presents a new, simple, accurate, and inexpensive practical methodology and experimental solution for the modeling of conventional (domestic and commercial facilities) photovoltaic generators (PVG), so that they can work at their maximum power point (MPP). The PVG may be a panel, an array of panels, or a photovoltaic field. As a starting restriction (actual) it has to be assumed that it is not possible to isolate the PVG variables dependence (mainly current, voltage, and hence power) with solar radiation and temperature, because they are highly correlated. This methodology proposes the modeling facility on its MPP by its MPP resistance (RMPP = VMPP/IMPP), being VMPP and IMPP the voltage and current of the PVG, respectively, at its MPP. The analysis shows, by simulation first and then experimentally, that RMPP does not present significant temperature dependencies, at least in the usual range. This important result allows us to model the PVG only in terms of solar radiation. From a set of experimental data, different models to estimate RMPP are proposed. The obtained results are very accurate. These models allow an immediate practical application that it is also developed in the paper: MPP tracker (MPPT) design by the calculation of the DC/DC converter duty cycle which places the PVG at its MPP directly and continuously. This new methodology and experimental system has been registered in the Spanish Patent and Trademark Office with the number P201530352. Copyright © 2015 John Wiley & Sons, Ltd.
The path of no return—Truncated protein N‐termini and current ignorance of their genesis
Authors: Fortelny Nikolaus , Pavlidis Paul , Overall Christopher M.
Published: May 2015

Almost all regulatory processes in biology ultimately lead to or originate from modifications of protein function. However, it is unclear to which extent each mechanism of regulation actually affects proteins and thus phenotypes. We assessed the extent of N‐terminal protein truncation in a global analysis of N‐terminomics data and find that most proteins have N‐terminally truncated proteoforms. Because N‐terminomics analyses do not identify the process generating the identified N‐termini, we compared identified termini to the three N‐termini generating events: protein cleavage, alternative translation, and alternative splicing. Of these, we sought to identify the most likely cause of N‐terminal protein truncations in the human proteome. We found that protease cleavage and alternative protein translation are the likely cause for most shortened proteoforms. However, the vast majority (about 90%) of N‐termini remain unexplained by any of these processes identified to date, so revealing large gaps in our knowledge of protein termini and their genesis. Further analysis and annotation of terminomics data is required, to which end we have created the TopFIND database, a major systematic annotation effort for protein termini. We outline the new features in version 3.0 of the updated database and the new bioinformatics tools available and encourage submission of generated data to fill current knowledge gaps.
Covariant Lyapunov vectors of a quasi‐geostrophic baroclinic model: analysis of instabilities and feedbacks
Authors: Schubert Sebastian , Lucarini Valerio
Published: May 2015

The classical approach for studying atmospheric variability is based on defining a background state and studying the linear stability of the small fluctuations around such a state. Weakly nonlinear theories can be constructed using higher order expansion terms. While these methods undoubtedly have great value for elucidating the relevant physical processes, they are unable to follow the dynamics of a turbulent atmosphere. We provide a first example of the extension of classical stability analysis to a nonlinearly evolving quasi‐geostrophic flow. The so‐called covariant Lyapunov vectors (CLVs) provide a covariant basis describing the directions of exponential expansion and decay of perturbations to the nonlinear trajectory of the flow. We use such a formalism to re‐examine the basic barotropic and baroclinic processes of the atmosphere with a quasi‐geostrophic beta‐plane two‐layer model in a periodic channel driven by a forced meridional temperature gradient ΔT. We explore three settings of ΔT, representative of relatively weak turbulence, well‐developed turbulence and intermediate conditions.

We construct the Lorenz energy cycle for each CLV describing the energy exchanges with the background state. A positive baroclinic conversion rate is a necessary but not sufficient condition for instability. Barotropic instability is present only for a few very unstable CLVs for large values of ΔT. Slowly growing and decaying hydrodynamic Lyapunov modes closely mirror the properties of the background flow. Following the classical necessary conditions for barotropic/baroclinic instability, we find a clear relationship between the properties of the eddy fluxes of a CLV and its instability. CLVs with positive baroclinic conversion seem to form a set of modes for constructing a reduced model of the atmospheric dynamics.
Pleuroparenchymal fibroelastosis: a rare interstitial lung disease
Authors: English John C. , Mayo John R. , Levy Robert , Yee John , Leslie Kevin O.
Published: May 2015

Pleuroparenchymal fibroelastosis (PPFE) is a newly described form of interstitial lung disease that originates in the upper lung zones and typically progresses to involve the entire lung. The disease may be idiopathic but is often associated with other pre‐ or coexisting conditions. Pneumothorax is a common complication and can occur at presentation or at other times during the course of the disease. Pathologically, interstitial fibrosis takes the form of a dense consolidation with some preservation of alveolar septal outlines and demonstrates a distinctly abrupt interface with residual normal lung. Unrecognized cases of PPFE may be incorrectly diagnosed as sarcoidosis, atypical idiopathic pulmonary fibrosis, or other unclassifiable interstitial pneumonias.
Advances on Modelling Riparian Vegetation—Hydromorphology Interactions
Authors: Solari L. , Van Oorschot M. , Belletti B. , Hendriks D. , Rinaldi M. , Vargas‐Luna A.
Published: May 2015

Riparian vegetation actively interacts with fluvial systems affecting river hydrodynamics, morphodynamics and groundwater. These interactions can be coupled because both vegetation and hydromorphology (i.e. the combined scientific study of hydrology and fluvial geomorphology) involve dynamic processes with similar temporal and spatial scales. To predict and assess the consequences of restoration measures, maintenance operations or human pressures in rivers, managers and planners may wish to model these interactions considering the different and interdisciplinary implications in the fields of ecology, geomorphology and hydrology. In this paper, we review models that are currently available and that incorporate the processes that relate riparian vegetation to hydromorphology. The models that are considered include those emphasizing hydraulic‐geomorphological processes (such as flow resistance, sediment transport and bank dynamics) as well as those emphasizing ecological processes (seed dispersal, plant survival, growth, succession and mortality). Models interpreting the coupled evolution between riparian vegetation and river morphology and groundwater are also presented. The aim is to provide an overview of current modelling capabilities and limitations and to identify future modelling challenges. Copyright © 2015 John Wiley & Sons, Ltd.