bluuebunny/crossref_metadata_2025 huggingface dataset:
Structural features of two major nucleolar organizer regions (NORs), Nor‐B1 and Nor‐B2, and chromosome‐specific rRNA gene expression in wheat
Authors: Handa Hirokazu , Kanamori Hiroyuki , Tanaka Tsuyoshi , Murata Kazuki , Kobayashi Fuminori , Robinson Stephen J. , Koh Chu S. , Pozniak Curtis J. , Sharpe Andrew G. , Paux Etienne ,   International Wheat Genome Sequencing Consortium, Wu Jianzhong , Nasuda Shuhei
Published: September 2018

Summary

The reference genome sequence of wheat ‘Chinese Spring’ (CS) is now available (IWGSC RefSeq v1.0), but the core sequences defining the nucleolar organizer regions (NORs) have not been characterized. We estimated that the total copy number of the rDNA units in the wheat genome is 11 160, of which 30.5%, 60.9% and 8.6% are located on Nor‐B1 (1B), Nor‐B2 (6B) and other NORs, respectively. The total length of the NORs is estimated to be 100 Mb, corresponding to approximately 10% of the unassembled portion of the genome not represented in RefSeq v1.0. Four subtypes (S1–S4) of the rDNA units were identified based on differences within the 3′ external transcribed spacer regions in Nor‐B1 and Nor‐B2, and quantitative PCR indicated locus‐specific variation in rDNA subtype contents. Expression analyses of rDNA subtypes revealed that S1 was predominantly expressed and S2 weakly expressed, in contrast to the relative abundance of rDNA subtypes in the wheat genome. These results suggest a regulation mechanism of differential rDNA expression based on sequence differences. S3 expression increased in the ditelosomic lines Dt1BL and Dt6BL, suggesting that S3 is subjected to chromosome‐mediated silencing. Structural differences were detected in the regions surrounding the NOR among homoeologous chromosomes of groups 1 and 6. The adjacent regions distal to the major NORs were expanded compared with their homoeologous counterparts, and the gene density of these expanded regions was relatively low. We provide evidence that these regions are likely to be important for autoregulation of the associated major NORs as well as silencing of minor NORs.
Immune receptor genes and pericentromeric transposons as targets of common epigenetic regulatory elements
Authors: Cambiagno Damián A. , Nota Florencia , Zavallo Diego , Rius Sebastián , Casati Paula , Asurmendi Sebastián , Alvarez María E.
Published: September 2018

Pattern recognition receptors (PRR) and nucleotide‐binding leucine‐rich repeat proteins (NLR) are major components of the plant immune system responsible for pathogen detection. To date, the transcriptional regulation of PRR/NLR genes is poorly understood. Some PRR/NLR genes are affected by epigenetic changes of neighboring transposable elements (TEs) (cis regulation). We analyzed whether these genes can also respond to changes in the epigenetic marks of distal pericentromeric TEs (trans regulation). We found that Arabidopsis tissues infected with Pseudomonas syringae pv. tomato (Pst) initially induced the expression of pericentromeric TEs, and then repressed it by RNA‐directed DNA methylation (RdDM). The latter response was accompanied by the accumulation of small RNAs (sRNAs) mapping to the TEs. Curiously these sRNAs also mapped to distal PRR/NLR genes, which were controlled by RdDM but remained induced in the infected tissues. Then, we used non‐infected mom1 (Morpheus’ molecule 1) mutants that expressed pericentromeric TEs to test if they lose repression of PRR/NLR genes. mom1 plants activated several PRR/NLR genes that were unlinked to MOM1‐targeted TEs, and showed enhanced resistance to Pst. Remarkably, the increased defenses of mom1 were abolished when MOM1/RdDM‐mediated pericentromeric TEs silencing was re‐established. Therefore, common sRNAs could control PRR/NLR genes and distal pericentromeric TEs and preferentially silence TEs when they are activated.
Limbal squamous cell carcinoma in a Rocky Mountain Horse: Case report and investigation of genetic contribution
Authors: Knickelbein Kelly E. , Lassaline Mary E. , Bellone Rebecca R.
Published: September 2018

Objective

To document a case of limbal squamous cell carcinoma (SCC) in a Rocky Mountain Horse stallion determined to be homozygous for the genetic risk factor (DDB2c.1013C>T) strongly associated with the disease in Haflinger and Belgian horses, and to determine the frequency of this allele in a larger population of Rocky Mountain Horses.

Animals studied

One privately owned Rocky Mountain Horse and 84 Rocky Mountain Horses screened for allelic frequency.

Procedures

A complete ophthalmic examination was performed on a Rocky Mountain Horse stallion for assessment of a mass affecting the right eye. A clinical diagnosis of suspected limbalSCCwas made, and routine keratoconjunctivectomy and adjunctive strontium irradiation were performed. Genotyping for theDDB2c.1013C > T(rs1139682898) risk variant was performed utilizing an allele‐specificPCRassay onDNAisolated from whole blood and hair follicles.

Results

Histopathology confirmed the limbal mass to be consistent withSCC. The horse was genotyped as homozygous for theDDB2c.1013C >Trisk variant. The frequency of the variant allele among a population of 84 Rocky Mountain Horses was found to be 0.20.

Conclusion

The Rocky Mountain Horse breed possesses theDDB2variant allele determined to be a significant risk factor for ocularSCCin the Haflinger and Belgian breeds. Genotyping additional Rocky Mountain Horses diagnosed with ocularSCCas well as confirmed healthy controls for this variant should be undertaken to determine whether a significant association exists between ocularSCCand the variant in the Rocky Mountain Horse breed.
Nanostructured biomedical selenium at the biological interface (Review)
Authors: Tan Victoria le Ching , Hinchman Angelica , Williams Richard , Tran Phong A. , Fox Kate
Published: September 2018

This paper critically reviews the current evidence of research in biomedical applications of selenium nanoparticles (SeNPs) and their effects at cellular and tissue levels. In recent years, interest in SeNPs as a natural trace element nanomaterial for nanomedicine has resulted in a number of studies evaluating their bioactivities, such as anticancer, antimicrobial, and antioxidant properties. Significant data have been generated to demonstrate the effectiveness of SeNPs alone or in combination with other reagents. Their activities are demonstrated through in vitro and in vivo experimentation; yet, the levels of efficacy need to be improved, particularly when compared with those of pharmaceutical drugs (such as antibiotics and cytotoxic chemotherapeutic drugs). However, promising evidence suggests decreased toxicity when using SeNPs, and more importantly their ability to perform as an interfacing biomaterial with cells and tissues. SeNPs have demonstrated unique antibacterial properties: they inhibit bacterial adhesion, growth, and/or quorum sensing and as a result prevent biofilm formation on medical devices, to name a few. Therefore, as with other nanomaterials, SeNPs warrant further study as part of the biomaterial-based therapeutic toolkit as an alternative to traditional pharmaceutical agents. This paper will provide a succinct review of recent studies on SeNPs to critically assess the findings in the light of effectiveness, particularly highlighting the roles of the cellular interface. Finally, an outlook of the potential of SeNPs will be presented to highlight the need for more intensive studies of material stability, mechanistic understanding at subcellular levels, and investigations into their combinational and/or synergistic effects with other bioactive reagents including pharmaceutical drugs.
Tailoring emergent spin phenomena in Dirac material heterostructures
Authors: Khokhriakov Dmitrii , Cummings Aron W. , Song Kenan , Vila Marc , Karpiak Bogdan , Dankert André , Roche Stephan , Dash Saroj P.
Published: September 2018

Dirac material–based heterostructures reveal enhanced spin-orbit coupling with an emerging spin texture.
Hydrogenation of terminal and internal olefins using a biowaste-derived heterogeneous cobalt catalyst
Authors: Scharnagl Florian Korbinian , Hertrich Maximilian Franz , Ferretti Francesco , Kreyenschulte Carsten , Lund Henrik , Jackstell Ralf , Beller Matthias
Published: September 2018

An active and renewable catalyst for olefin hydrogenation was obtained by inclusion of cobalt in a carbon matrix derived from the pyrolysis of chitosan.
Magic angle spinning spheres
Authors: Chen Pinhui , Albert Brice J. , Gao Chukun , Alaniva Nicholas , Price Lauren E. , Scott Faith J. , Saliba Edward P. , Sesti Erika L. , Judge Patrick T. , Fisher Edward W. , Barnes Alexander B.
Published: September 2018

Spherical rotors can be used for magic angle spinning nuclear magnetic resonance.
Facile manufacture of porous organic framework membranes for precombustion CO
2
capture
Authors: Shan Meixia , Liu Xinlei , Wang Xuerui , Yarulina Irina , Seoane Beatriz , Kapteijn Freek , Gascon Jorge
Published: September 2018

Ultrastable and highly H
2
-selective porous organic framework membranes were successfully synthesized by interfacial polymerization.
Enhancing FcγR-mediated antibody effector function during persistent viral infection
Authors: Wieland Andreas , Kamphorst Alice O. , Valanparambil Rajesh M. , Han Jin-Hwan , Xu Xiaojin , Choudhury Biswa P. , Ahmed Rafi
Published: September 2018

High antigen expression or use of afucosylated antibodies enables antibody-mediated depletion during chronic viral infection.
In Vitro
Activity of Ceftazidime-Avibactam and Aztreonam-Avibactam against OXA-48-Carrying Enterobacteriaceae Isolated as Part of the International Network for Optimal Resistance Monitoring (INFORM) Global Surveillance Program from 2012 to 2015
Authors: Kazmierczak Krystyna M. , Bradford Patricia A. , Stone Gregory G. , de Jonge Boudewijn L. M. , Sahm Daniel F.
Published: September 2018

Enterobacteriaceae
producing the Ambler class D OXA-48 carbapenemase, combined with additional resistance mechanisms, such as permeability defects or cocarriage of class A, B, or C β-lactamases, can become highly resistant to most β-lactams currently in use, including carbapenems. A total of 45,872
Enterobacteriaceae
clinical isolates collected in 39 countries as part of the International Network for Optimal Resistance Monitoring (INFORM) global surveillance study in 2012 to 2015 were tested for susceptibility to β-lactams and comparator agents using the Clinical and Laboratory Standards Institute broth microdilution methodology and screened for the presence of β-lactamases.
Activity of Moxifloxacin against
Mycobacterium tuberculosis
in Acid Phase and Nonreplicative-Persister Phenotype Phase in a Hollow-Fiber Infection Model
Authors: Louie Arnold , Duncanson Brandon , Myrick Jenny , Maynard Michael , Nole Jocelyn , Brown David , Schmidt Stephan , Neely Michael , Scanga C. A. , Peloquin Charles , Drusano G. L.
Published: September 2018

A major goal for improving tuberculosis therapy is to identify drug regimens with improved efficacy and shorter treatment durations. Shorter therapies improve patient adherence to the antibiotic regimens, which, in turn, decreases resistance emergence.
Performance of Commercially Available Serological Screening Tests for Human T-Cell Lymphotropic Virus Infection in Brazil
Authors: da Silva Brito Vanessa , Santos Fred Luciano Neves , Gonçalves Noilson Lazaro Sousa , Araujo Thessika Hialla Almeida , Nascimento Davi Silva Vale , Pereira Felicidade Mota , Boa-Sorte Ney Cristian Amaral , Grassi Maria Fernanda Rios , Caterino-de-Araujo Adele , Galvão-Castro Bernardo
Published: September 2018

Serological screening for human T-cell lymphotropic virus type 1 (HTLV-1) is usually performed using enzyme-linked immunosorbent assay (ELISA), particle agglutination, or chemiluminescence assay kits. Due to an antigen matrix improvement entailing the use of new HTLV antigens and changes in the format of HTLV screening tests, as well as newly introduced chemiluminescence assays (CLIAs), a systematic evaluation of the accuracy of currently available commercial tests is warranted.
Detection of Viruses in Clinical Samples by Use of Metagenomic Sequencing and Targeted Sequence Capture
Authors: Wylie Kristine M. , Wylie Todd N. , Buller Richard , Herter Brandi , Cannella Maria T. , Storch Gregory A.
Published: September 2018

Metagenomic shotgun sequencing (MSS) is a revolutionary approach to viral diagnostic testing that allows simultaneous detection of a broad range of viruses, detailed taxonomic assignment, and detection of mutations associated with antiviral drug resistance. To enhance sensitivity for virus detection, we previously developed ViroCap, a targeted sequence capture panel designed to enrich nucleic acid from a comprehensive set of eukaryotic viruses prior to sequencing.
Direct Detection of Emergent Fungal Pathogen Candida auris in Clinical Skin Swabs by SYBR Green-Based Quantitative PCR Assay
Authors: Sexton D. Joseph , Kordalewska Milena , Bentz Meghan L. , Welsh Rory M. , Perlin David S. , Litvintseva Anastasia P.
Published: September 2018

The recent emergence of the multidrug-resistant and pathogenic yeast
Candida auris
continues to cause public health concern worldwide.
C. auris
is alarming because it causes health care-associated outbreaks and can establish invasive infections with high mortality rates.
Mitral valve prolapse and sudden cardiac death: a systematic review and meta-analysis
Authors: Nalliah Chrishan J , Mahajan Rajiv , Elliott Adrian D , Haqqani Haris , Lau Dennis H , Vohra Jitendra K , Morton Joseph B , Semsarian Christopher , Marwick Thomas , Kalman Jonathan M , Sanders Prashanthan
Published: September 2018

Objectives

Mitral valve prolapse (MVP) is commonly observed as a benign finding. However, the literature suggests that it may be associated with sudden cardiac death (SCD). We performed a meta-analysis and systematic review to determine the: (1) prevalence of MVP in the general population; (2) prevalence of MVP in all SCD and unexplained SCD; (3) incidence of SCD in MVP and (4) risk factors for SCD.

Methods

The English medical literature was searched for: (1) MVP community prevalence; (2) MVP prevalence in SCD cohorts; (3) incidence SCD in MVP and (4) SCD risk factors in MVP. Thirty-four studies were identified for inclusion. This study was registered with PROSPERO (CRD42018089502).

Results

The prevalence of MVP was 1.2% (95% CI 0.5 to 2.0) in community populations. Among SCD victims, the cause of death remained undetermined in 22.1% (95% CI 13.4 to 30.7); of these, MVP was observed in 11.7% (95% CI 5.8 to 19.1). The incidence of SCD in the MVP population was 0.14% (95% CI 0.1 to 0.3) per year. Potential risk factors for SCD include bileaflet prolapse, ventricular fibrosis complex ventricular ectopy and ST-T wave abnormalities.

Conclusion

The high prevalence of MVP in cohorts of unexplained SCD despite low population prevalence provides indirect evidence of an association of MVP with SCD. The absolute number of people exposed to the risk of SCD is significant, although the incidence of life-threatening arrhythmic events in the general MVP population remains low. High-risk features include bileaflet prolapse, ventricular fibrosis, ST-T wave abnormalities and frequent complex ventricular ectopy.

Trial registration

PROSPERO (CRD42018089502).
Birth weight in pregnancies complicated by maternal heart disease
Authors: Cauldwell Matthew , Steer Philip , Sterrenburg Monique , Wallace Suzanne , Malin Gemma , Ulivi Gemma , Everett Thomas , Jakes Adam Daniel , Head Catherine E G , Mohan Aarthi R , Haynes Sophie , Simpson Margaret , Brennand Janet , Johnson Mark R
Published: September 2018

Objective

To assess median and percentile birthweight distribution in women with various groups of heart disease relative to a contemporaneous comparison group.

Methods

Data on birth weight and gestational age were collected from 1321 pregnancies ≥24 weeks’ gestation in 1053 women with heart disease from seven UK maternity units. Women were assigned to one of 16 groups according to their cardiac lesion. In units where it was possible, data on two births, one delivering before and one after index cases, were collected, giving 2307 comparators. Birthweight percentiles (corrected for gestational age, sex and parity) were calculated using Aberdeen norms. We assessed the association of birth weight with cardiac lesion, maternal hypoxaemia (saturations <90%), systemic ventricular function and beta-blockers.

Results

1321 pregnancies in women with heart disease and 2307 comparators were studied. Almost all groups with heart disease had lower median and percentile birth weights than comparators, significantly in 10 groups, the biggest effect seen in women with Fontan circulation, pulmonary hypertension, prosthetic heart valves, systemic right ventricle, Marfan syndrome, repaired tetralogy of Fallot and cardiomyopathy (in that order). In 307 pregnancies, women took beta-blockers; median birth weight adjusted for maternal age, parity and the effect of the cardiac lesion was 3116.7 g (IQR 790.4) when beta-blockers were used and 3354.3 g (IQR 634.1) when they were not (p<0.001). 17 women had saturations <90%, and median birth weight was significantly lower, 3105.4 g (IQR 1288.9) versus 3387.7 g (IQR 729.8) (p=0.006).

Conclusion

Our findings identify specific groups of women with heart disease at risk of having a small baby.
Molecular and clinical analyses of two patients with UPD(16)mat detected by screening 94 patients with Silver-Russell syndrome phenotype of unknown aetiology
Authors: Inoue Takanobu , Yagasaki Hideaki , Nishioka Junko , Nakamura Akie , Matsubara Keiko , Narumi Satoshi , Nakabayashi Kazuhiko , Yamazawa Kazuki , Fuke Tomoko , Oka Akira , Ogata Tsutomu , Fukami Maki , Kagami Masayo
Published: September 2018

Background

Recently, a patient with maternal uniparental disomy of chromosome 16 (UPD(16)mat) presenting with Silver-Russell syndrome (SRS) phenotype was reported. SRS is characterised by growth failure and dysmorphic features.

Objective

To clarify the prevalence of UPD(16)mat in aetiology-unknown patients with SRS phenotype and phenotypic differences between UPD(16)mat and SRS.

Methods

We studied 94 patients with SRS phenotype of unknown aetiology. Sixty-three satisfied the Netchine-Harbison clinical scoring system (NH-CSS) criteria, and 25 out of 63 patients showed both protruding forehead and relative macrocephaly (clinical SRS). The remaining 31 patients met only three NH-CSS criteria, but were clinically suspected as having SRS. To detect UPD(16)mat, we performed methylation analysis for theZNF597:TSS-differentially methylated region (DMR) on chromosome 16 and subsequently performed microsatellite, SNP array and exome analyses in the patients with hypomethylatedZNF597:TSS-DMR.

Results

We identified two patients (2.1%) with a mixture of maternal isodisomy and heterodisomy of chromosome 16 in 94 aetiology-unknown patients with SRS phenotype. Both patients exhibited preterm birth and prenatal and postnatal growth failure. The male patient had ventricular septal defect and hypospadias. Whole-exome sequencing detected no gene mutations related to their phenotypes.

Conclusion

We suggest considering genetic testing for UPD(16)mat in SRS phenotypic patients without known aetiology.
Resting metabolic rate in muscular physique athletes: validity of existing methods and development of new prediction equations
Authors: Tinsley Grant M. , Graybeal Austin J. , Moore M. Lane
Published: September 2018

Estimation of resting metabolic rate (RMR) is an important step for prescribing an individual’s energy intake. The purpose of this study was to evaluate the validity of portable indirect calorimeters and RMR prediction equations in muscular physique athletes. Twenty-seven males (n = 17; body mass index (BMI): 28.8 ± 2.0 kg/m2; body fat: 12.5% ± 2.7%) and females (n = 10; BMI: 22.8 ± 1.6 kg/m2; body fat: 19.2% ± 3.4%) were evaluated. The reference RMR value was obtained from the ParvoMedics TrueOne 2400 indirect calorimeter, and the Cosmed Fitmate and Breezing Metabolism Tracker provided additional RMR estimates. Existing RMR prediction equations based on body weight (BW) or dual-energy X-ray absorptiometry fat-free mass (FFM) were also evaluated. Errors in RMR estimates were assessed using validity statistics, including t tests with Bonferroni correction, linear regression, and calculation of the standard error of the estimate, total error, and 95% limits of agreement. Additionally, new prediction equations based on BW (RMR (kcal/day) = 24.8 × BW (kg) + 10) and FFM (RMR (kcal/day) = 25.9 × FFM (kg) + 284) were developed using stepwise linear regression and evaluated using leave-one-out cross-validation. Nearly all existing BW- and FFM-based prediction equations, as well as the Breezing Tracker, did not exhibit acceptable validity and typically underestimated RMR. The ten Haaf and Weijs (PLoS ONE, 9: e1084602014 (2014)) and Cunningham (1980) (Am. J. Clin. Nutr. 33: 2372–2374 (1980)) FFM-based equations may produce acceptable RMR estimates, although the Cosmed Fitmate and newly developed BW- and FFM-based equations may be most suitable for RMR estimation in male and female physique athletes. Future research should provide additional external cross-validation of the newly developed equations to refine the ability to predict RMR in physique athletes.
Pixel-level statistical analyses of prescribed fire spread
Authors: Currie M. , Speer K. , Hiers J.K. , O’Brien J.J. , Goodrick S. , Quaife B.
Published: September 2018

Wildland fire dynamics are a complex three-dimensional turbulent process. Cellular automata (CA) is an efficient tool to predict fire dynamics, but the main parameters of the method are challenging to estimate. To overcome this challenge, we compute statistical distributions of the key parameters of a CA model using infrared images from controlled burns. Moreover, we apply this analysis to different spatial scales and compare the experimental results with a simple statistical model. By performing this analysis and making this comparison, several capabilities and limitations of CA are revealed.
Additive biomass equations for slash pine trees: comparing three modeling approaches
Authors: Zhao Dehai , Westfall James , Coulston John W. , Lynch Thomas B. , Bullock Bronson P. , Montes Cristian R.
Published: September 2018

Both aggregative and disaggregative strategies were used to develop additive nonlinear biomass equations for slash pine (Pinus elliottii Engelm. var. elliottii) trees in the southeastern United States. In the aggregative approach, the total tree biomass equation was specified by aggregating the expectations of component biomass models, and their parameters were estimated by jointly fitting all component and total biomass equations using weighted nonlinear seemingly unrelated regression (NSUR) (SUR1) or by jointly fitting component biomass equations using weighted NSUR (SUR2). In an alternative disaggregative approach (DRM), the biomass component proportions were modeled using Dirichlet regression, and the estimated total tree biomass was disaggregated into biomass components based on their estimated proportions. There was no single system to predict biomass that was best for all components and total tree biomass. The ranking of the three systems based on an array of fit statistics followed the order of SUR2 > SUR1 > DRM. All three systems provided more accurate biomass predictions than previously published equations.
INVESTIGATION OF MECHANICAL BEHAVIOR OF NiTi STENT UNDER DIFFERENT LOADINGS
Authors: MEHRABI REZA , PARIZI FATEMEH SALEMIZADEH
Published: September 2018

Biocompatible stent implants that have been made of shape memory alloys (SMA) are being used in arteries which are restoring normal blood flow. A high failure rate of stent implants in femoral artery causes the investigation of the mechanical behavior of stent implants, and its design and manufacturing, a necessity study. In this paper, two different stent designs, with different geometries, have been simulated. One is a Diamond-shaped profile stent and the other one is a V-shaped profile stent. These stents have been simulated under different loadings such as tensile and bending loadings that are very similar to the loading environment imposed by the arterial wall and blood flow. Two different temperatures have been selected to investigate superelasticity as well as shape memory effect of NiTi stents. During unloading for the shape memory case, the residual strains are recovered by heating the stents. The verified model based on microplane model is numerically considered for simulation of the stents. Numerical results show that the V-shaped stent design stretches more than the Diamond-shaped stent design under tensile loading. In addition, the V-shaped stent bends more than Diamond-shaped stent under the same bending loading, which shows more flexibility.
Atomic systems for operators
Authors: Poumai Khole Timothy , Jahan Shah
Published: September 2018

Gavruta [L. Gavruta, Frames for operators, Appl. Comput. Harmon. Anal. 32 (2012) 139–144] introduced the notion of [Formula: see text]-frame and atomic system for an operator [Formula: see text] in Hilbert spaces. We extend these notions to Banach spaces and obtain various new results. A necessary and sufficient condition for the existence of an atomic system for an operator [Formula: see text] in a Banach space is given. Also, a characterization for the family of local atoms of subspaces of Banach spaces has been given. Further, we give methods to construct an atomic system for an operator [Formula: see text] from a given Bessel sequence and an [Formula: see text]-Bessel sequence. Finally, a result related to stability of atomic system for an operator [Formula: see text] in a Banach space has been given.
Exploring Symmetrical and Asymmetrical Dirichlet Priors for Latent Dirichlet Allocation
Authors: Syed Shaheen , Spruit Marco
Published: September 2018

Latent Dirichlet Allocation (LDA) has gained much attention from researchers and is increasingly being applied to uncover underlying semantic structures from a variety of corpora. However, nearly all researchers use symmetrical Dirichlet priors, often unaware of the underlying practical implications that they bear. This research is the first to explore symmetrical and asymmetrical Dirichlet priors on topic coherence and human topic ranking when uncovering latent semantic structures from scientific research articles. More specifically, we examine the practical effects of several classes of Dirichlet priors on 2000 LDA models created from abstract and full-text research articles. Our results show that symmetrical or asymmetrical priors on the document–topic distribution or the topic–word distribution for full-text data have little effect on topic coherence scores and human topic ranking. In contrast, asymmetrical priors on the document–topic distribution for abstract data show a significant increase in topic coherence scores and improved human topic ranking compared to a symmetrical prior. Symmetrical or asymmetrical priors on the topic–word distribution show no real benefits for both abstract and full-text data.
A study of methods to prevent piping and erosion in buffer materials intended for a vertical deposition hole at the Horonobe Underground Research Laboratory
Authors: Jo Mayumi , Ono Makoto , Nakayama Masashi , Asano Hidekazu , Ishii Tomoko
Published: September 2018

Piping and erosion phenomena are serious problems affecting the integrity of buffer materials, which are an element of engineered barrier systems in the geological disposal of high-level radioactive waste. In this study, the outflow behaviour and the condition of buffer materials are investigated using a test pit drilled into host rock at the Horonobe Underground Research Laboratory to consider countermeasures to contain the outflow of the buffer material. The results are as follows: (1) Piping and erosion phenomena occur irrespective of the injection flow rate. However, when the rate is small, the buffer material is considered to be self-repairing and the outflow of the buffer material can be suppressed. (2) When the injection water contains large amounts of electrolytes, the surface of the buffer material peels off and precipitates, probably decreasing the waterproof performance. (3) Bentonite pellets are likely to be an effective countermeasure against piping and erosion.
The limits of heritage stone designation
Authors: Cooper Barry J.
Published: September 2018

Heritage stone was initially considered in terms of building stone; however, the use of natural stone extends much more widely into utilitarian applications, implements by prehistoric humans as well as decorative stones and gemstones. Nevertheless, there are limits to heritage stone designation where it may seem that recognition of a Global Heritage Stone Resource is inappropriate despite some favourable aspects.
Pathophysiology, adaptation, and imaging of the right ventricle in Fontan circulation
Authors: Files Matthew D. , Arya Bhawna
Published: September 2018

The Fontan procedure, which creates a total cavopulmonary anastomosis and represents the final stage of palliation for hypoplastic left heart syndrome, generates a unique circulation relying on a functionally single right ventricle (RV). The RV pumps blood in series around the systemic and pulmonary circulation, which requires adaptations to the abnormal volume and pressure loads. Here, we provide a complete review of RV adaptations as the RV assumes the role of the systemic ventricle, the progression of RV dysfunction to a distinct pattern of heart failure unique to this disease process, and the assessment and management strategies used to protect and rehabilitate the failing RV of Fontan circulation.
Implications for understanding ischemic stroke as a sexually dimorphic disease: the role of pial collateral circulations
Authors: Li Zhaojin , Tremble Sarah M. , Cipolla Marilyn J.
Published: September 2018

We investigated structural and functional differences in primary and pial collateral circulations in adult normotensive male and female Wistar rats. Male ( n = 10) and female ( n = 7) rats were subjected to middle cerebral artery (MCA) occlusion and changes in relative cerebral blood flow in MCA and pial collateral territories were measured by multisite laser-Doppler flowmetry. Rats were then transcardially perfused with a mixture of carbon black and latex, perfusion fixed, and imaged to compare primary and pial collateral structure between male ( n = 4) and female ( n = 3) rats, including lumen diameters and number. To study pial collateral function, leptomeningeal anastomoses (LMAs) were isolated and pressurized from male ( n = 7) and female ( n = 6) rats. Myogenic tone and reactivity to pressure, vascular function to pharmacological activator, or inhibitor of ion channels was measured and compared. There was no difference between relative cerebral blood flow in both MCA and pial collateral territories during occlusion and reperfusion between groups. Compared with male LMAs, female LMAs had similar myogenic tone (24.0 ± 7.3% vs. 16.0 ± 3.7%, P > 0.05) and reactivity to increased pressure and similar vascular responses to vasoconstrictive and vasodilatory stimuli. Additionally, compared with female LMAs, male LMAs had similar numbers (21 ± 1 vs. 20 ± 2, P > 0.05) and diameters (30.5 ± 2.0 vs. 26.2 ± 0.6 μm, P > 0.05), and no sex difference was detected in the diameter of arterial segments of circle of Willis. Together, our data establish no sex difference of cerebral collateral structure or function, suggesting that the reduced severity of stroke outcome in female rats is not likely due to differences in the cerebral collateral circulation.

NEW & NOTEWORTHY Our work compared the function of leptomeningeal anastomoses between male and female adult normotensive rats with no sex difference found. We also confirmed no sex difference in primary and pial collateral structure in Wistar rats. Our findings suggest that the reduced severity of stroke in premenopausal women and reproductively intact female rodents is not likely due to improved primary and pial collateral circulations.
Extracellular matrix in cardiovascular pathophysiology
Authors: Bloksgaard Maria , Lindsey Merry , Martinez-Lemus Luis A.
Published: September 2018

The extracellular matrix (ECM) actively participates in diverse aspects of cardiovascular development and physiology as well as during disease development and progression. ECM roles are determined by its physical and mechanical properties and by its capacity to both release bioactive signals and activate cell signaling pathways. The ECM serves as a storage depot for a wide variety of molecules released in response to injury or with aging. Indeed, there is a plethora of examples describing how cells react to or modify ECM stiffness, how cells initiate intracellular signaling pathways, and how cells respond to the ECM. This Perspectives article reviews the contributions of 21 articles published in the American Journal of Physiology-Heart and Circulatory Physiology in response to a Call for Papers on this topic. Here, we summarize the contributions of these studies focused on the cardiac and vascular ECM. We highlight the translational importance of these studies and conclude that the ECM is a critical component of both the heart and vasculature. Readers are urged to examine and learn from this special Call for Papers.
Chronic intermittent nicotine delivery via lung alveolar region-targeted aerosol technology produces circadian pharmacokinetics in rats resembling human smokers
Authors: Shao Xuesi M. , Liu Siyu , Lee Eon S. , Fung David , Pei Hua , Liang Jing , Mudgway Ross , Zhang Jingxi , Feldman Jack L. , Zhu Yifang , Louie Stan , Xie Xinmin S.
Published: September 2018

Cigarette smoke is an aerosol containing microparticles that carry nicotine into the lung alveolar region where nicotine is rapidly absorbed into circulation. Nicotine exposure in smokers is a chronic intermittent process, with episodic intake during wakefulness and abstinence during sleep resulting in circadian fluctuation of blood nicotine levels. We developed an integrated platform where freely moving rodents can be exposed to episodic nicotine aerosol on an investigator-designed schedule. Plasma nicotine and its metabolite cotinine levels were determined with a LC-MS/MS method. We characterized the aerosol in the breathing zone of the rodent exposure chamber. The droplet-size distribution was within the respirable diameter range. The system can generate a wide range of nicotine concentrations in air that meet a variety of experimental needs. Rats were exposed to nicotine aerosol once every half hour in the dark phase of 12:12-h light-dark cycles for 10 days. We optimized the parameters of aerosol generation and exposure: plasma nicotine and cotinine concentrations reached 30–35 and 190–240 ng/ml, respectively. The nicotine levels and circadian patterns resembled the pharmacokinetic pattern of human smokers. In summary, we developed an aerosol system that can produce clinically relevant chronic intermittent nicotine exposure in unanesthetized, unrestrained rodents with route of administration and circadian blood pharmacokinetics resembling human smokers. This methodology is a novel tool for understanding the health effects of chronic intermittent nicotine exposure such as with tobacco cigarettes and electronic cigarettes for studies of behavior, pharmacology and toxicology, nicotine addiction, tobacco-related diseases, and teratogenicity, and for the discovery of therapeutics.

NEW & NOTEWORTHY We developed a lung alveolar region-targeted aerosol method and a system that provides chronic intermittent nicotine exposure in freely moving rodents. The method produces in rodents clinically relevant nicotine exposure with the route and circadian pharmacokinetics resembling human smokers. This method is a novel tool for understanding the health impacts of chronic nicotine exposures such as with tobacco cigarettes and electronic cigarettes, for studying nicotine pharmacology, toxicology, addiction, and tobacco-related diseases, and for the discovery of therapeutics.
Passive stretch regulates skeletal muscle glucose uptake independent of nitric oxide synthase
Authors: Kerris Jarrod P. , Betik Andrew C. , Li Jinhua , McConell Glenn K.
Published: September 2018

Skeletal muscle contraction increases glucose uptake via an insulin-independent mechanism. Signaling pathways arising from mechanical strain are activated during muscle contractions, and mechanical strain in the form of passive stretching stimulates glucose uptake. However, the exact mechanisms regulating stretch-stimulated glucose uptake are not known. Since nitric oxide synthase (NOS) has been implicated in the regulation of glucose uptake during ex vivo and in situ muscle contractions and during exercise, and NO is increased with stretch, we examined whether the increase in muscle glucose uptake during stretching involves NOS. We passively stretched isolated extensor digitorum longus muscles (15 min at ~100–130 mN) from control mice and mice lacking either neuronal NOSµ (nNOSµ) or endothelial NOS (eNOS) isoforms, as well as used pharmacological inhibitors of NOS. Stretch significantly increased muscle glucose uptake appoximately twofold ( P < 0.05), and this was unaffected by the presence of the NOS inhibitors NG-monomethyl-l-arginine (100 µM) or NG-nitro-l-arginine methyl ester (100 µM). Similarly, stretch-stimulated glucose uptake was not attenuated by deletion of either eNOS or nNOSµ isoforms. Furthermore, stretching failed to increase skeletal muscle NOS enzymatic activity above resting levels. These data clearly demonstrate that stretch-stimulated skeletal muscle glucose uptake is not dependent on NOS.

NEW & NOTEWORTHY Passive stretching is known to activate muscle glucose uptake through mechanisms that partially overlap with contraction. We report that genetic knockout of endothelial nitric oxide synthase (NOS) or neuronal NOS or pharmacological NOS inhibition does not affect stretch-stimulated glucose uptake. Passive stretch failed to increase NOS activity above resting levels. This information is important for the study of signaling pathways that regulate stretch-stimulated glucose uptake and indicate that NOS should be excluded as a potential signaling factor in this regard.
Epigenetics of metabolic syndrome
Authors: Carson Caryn , Lawson Heather A.
Published: September 2018

The dramatic increase in global prevalence of metabolic disease is inexplicable when considering only environmental or only genetic factors, leading to the need to explore the possible roles of epigenetic factors. A great deal of progress has been made in this interdisciplinary field in recent years, with many studies investigating various aspects of the metabolic syndrome and its associated epigenetic changes. Rodent models of metabolic diseases have been particularly illuminating because of the ability to leverage tools such as genetic and environmental modifications. The current review summarizes recent breakthroughs regarding epigenetic markers in studies of obesity, Type II diabetes, and cardiovascular disease, the three major disorders associated with metabolic syndrome. We also discuss open questions and future directions for integrating genomic, epigenomic, and phenotypic big biodata toward understanding metabolic syndrome etiology.
CDK4/6 Inhibitor as a Novel Therapeutic Approach for Advanced Bladder Cancer Independently of RB1 Status
Authors: Rubio Carolina , Martínez-Fernández Mónica , Segovia Cristina , Lodewijk Iris , Suarez-Cabrera Cristian , Segrelles Carmen , López-Calderón Fernando , Munera-Maravilla Ester , Santos Mirentxu , Bernardini Alejandra , García-Escudero Ramón , Lorz Corina , Gómez-Rodriguez Maria José , de Velasco Guillermo , Otero Irene , Villacampa Felipe , Guerrero-Ramos Felix , Ruiz Sergio , de la Rosa Federico , Domínguez-Rodríguez Sara , Real Francisco X. , Malats Núria , Castellano Daniel , Dueñas Marta , Paramio Jesus M.
Published: September 2018

Purpose:

Bladder cancer is a clinical and social problem due to its high incidence and recurrence rates. It frequently appears in elderly patients showing other medical comorbidities that hamper the use of standard chemotherapy. We evaluated the activity of CDK4/6 inhibitor as a new therapy for patients unfit for cisplatin (CDDP).

Experimental Design:

Bladder cancer cell lines were tested for in vitro sensitivity to CDK4/6 inhibition. A novel metastatic bladder cancer mouse model was developed and used to test its in vivo activity.

Results:

Cell lines tested were sensitive to CDK4/6 inhibition, independent on RB1 gene status. Transcriptome analyses and knockdown experiments revealed a major role for FOXM1 in this response. CDK4/6 inhibition resulted in reduced FOXM1 phosphorylation in vitro and in vivo and showed synergy with CDDP, allowing a significant tumor regression. FOXM1 exerted important oncogenic roles in bladder cancer.

Conclusions:

CDK4/6 inhibitors, alone or in combination, are a novel therapeutic strategy for patients with advanced bladder cancer previously classified as unfit for current treatment options.
Selective TRK Inhibitor CH7057288 against TRK Fusion-Driven Cancer
Authors: Tanaka Hiroshi , Sase Hitoshi , Tsukaguchi Toshiyuki , Hasegawa Masami , Tanimura Hiromi , Yoshida Miyuki , Sakata Kiyoaki , Fujii Toshihiko , Tachibana Yukako , Takanashi Kenji , Higashida Atsuko , Hasegawa Kiyoshi , Ono Yoshiyuki , Oikawa Nobuhiro , Mio Toshiyuki
Published: September 2018

Members of the tropomyosin receptor kinase (TRK) family are expressed in their constitutively activated forms as a result of a gene fusion that occurs across a wide variety of cancer types. We have identified CH7057288 as a potent and selective TRK inhibitor that belongs to a novel chemical class. CH7057288 showed selective inhibitory activity against TRKA, TRKB, and TRKC in cell-free kinase assays and suppressed proliferation of TRK fusion–positive cell lines, but not that of TRK-negative cell lines. Strong in vivo tumor growth inhibition was observed in subcutaneously implanted xenograft tumor models of TRK fusion–positive cells. Furthermore, in an intracranial implantation model mimicking brain metastasis, CH7057288 significantly induced tumor regression and improved event-free survival. Recently, resistant mutations in the kinase domain of TRK have been reported in patients who show disease progression after treatment with the TRK inhibitors now under clinical development. Our compound maintained similar levels of in vitro and in vivo activity against one of these resistant mutants as it did to wild-type TRK. An X-ray crystal structure of the TRKA and CH7057288 complex supported the activity against the mutant. In addition, gene expression analysis revealed that CH7057288 suppressed MAPK and E2F pathways as downstream signaling of TRK fusion. Therefore, CH7057288 could be a promising therapeutic agent for TRK fusion–positive cancer.
Targeting the BRD4-HOXB13 Coregulated Transcriptional Networks with Bromodomain-Kinase Inhibitors to Suppress Metastatic Castration-Resistant Prostate Cancer
Authors: Nerlakanti Niveditha , Yao Jiqiang , Nguyen Duy T. , Patel Ami K. , Eroshkin Alexey M. , Lawrence Harshani R. , Ayaz Muhammad , Kuenzi Brent M. , Agarwal Neha , Chen Yunyun , Gunawan Steven , Karim Rezaul M. , Berndt Norbert , Puskas John , Magliocco Anthony M. , Coppola Domenico , Dhillon Jasreman , Zhang Jingsong , Shymalagovindarajan Subramaniam , Rix Uwe , Kim Youngchul , Perera Ranjan , Lawrence Nicholas J. , Schonbrunn Ernst , Mahajan Kiran
Published: September 2018

Resistance to androgen receptor (AR) antagonists is a significant problem in the treatment of castration-resistant prostate cancers (CRPC). Identification of the mechanisms by which CRPCs evade androgen deprivation therapies (ADT) is critical to develop novel therapeutics. We uncovered that CRPCs rely on BRD4-HOXB13 epigenetic reprogramming for androgen-independent cell proliferation. Mechanistically, BRD4, a member of the BET bromodomain family, epigenetically promotes HOXB13 expression. Consistently, genetic disruption of HOXB13 or pharmacological suppression of its mRNA and protein expression by the novel dual-activity BET bromodomain-kinase inhibitors directly correlates with rapid induction of apoptosis, potent inhibition of tumor cell proliferation and cell migration, and suppression of CRPC growth. Integrative analysis revealed that the BRD4-HOXB13 transcriptome comprises a proliferative gene network implicated in cell-cycle progression, nucleotide metabolism, and chromatin assembly. Notably, although the core HOXB13 target genes responsive to BET inhibitors (HOTBIN10) are overexpressed in metastatic cases, in ADT-treated CRPC cell lines and patient-derived circulating tumor cells (CTC) they are insensitive to AR depletion or blockade. Among the HOTBIN10 genes, AURKB and MELK expression correlates with HOXB13 expression in CTCs of mCRPC patients who did not respond to abiraterone (ABR), suggesting that AURKB inhibitors could be used additionally against high-risk HOXB13-positive metastatic prostate cancers. Combined, our study demonstrates that BRD4-HOXB13-HOTBIN10 regulatory circuit maintains the malignant state of CRPCs and identifies a core proproliferative network driving ADT resistance that is targetable with potent dual-activity bromodomain-kinase inhibitors.
Epigenetic Silencing of THY1 Tracks the Acquisition of the Notch1–EGFR Signaling in a Xenograft Model of CD44+/CD24low/CD90+ Myoepithelial Cells
Authors: Montanari Micaela , Carbone Maria Rita , Coppola Luigi , Giuliano Mario , Arpino Grazia , Lauria Rossella , Nardone Agostina , Leccia Felicia , Trivedi Meghana V. , Garbi Corrado , Bianco Roberto , Avvedimento Enrico V. , De Placido Sabino , Veneziani Bianca Maria
Published: September 2018

The surface glycoprotein THY is a marker of myoepithelial precursor cells, which are basal cells with epithelial–mesenchymal intermediate phenotype originating from the ectoderm. Myoepithelial precursor cells are lost during progression from in situ to invasive carcinoma. To define the functional role of Thy1-positive cells within the myoepithelial population, we tracked Thy1 expression in human breast cancer samples, isolated THY1-positive myoepithelial progenitor cells (CD44+/CD24low/CD90+), and established long-term cultures (parental cells). Parental cells were used to generate a xenograft model to examine Thy1 expression during tumor formation. Post-transplantation cell cultures lost THY1 expression through methylation at the THY1 locus and this is associated with an increase in EGFR and NOTCH1 transcript levels. Thy1-low cells are sensitive to the EGFR/HER2 dual inhibitor lapatinib. High THY1 expression is associated with poorer relapse-free survival in patients with breast cancer. THY1 methylation may track the shift of bipotent progenitors into differentiated cells. Thy1 is a good candidate biomarker in basal-like breast cancer.

Implications:

Our findings provide evidence that THY1 expression is lost in xenografts due to promoter methylation. Thy1-low cells with increased EGFR and Notch1 expression are responsive to target therapy. Because DNA methylation is often altered in early cancer development, candidate methylation markers may be exploited as biomarkers for basal-like breast cancer.