bluuebunny/crossref_metadata_2025 huggingface dataset:
Plasma Neutrophil Gelatinase-Associated Lipocalinin in the General Population
Authors: Lindberg Søren , Jensen Jan S. , Mogelvang Rasmus , Pedersen Sune H. , Galatius Søren , Flyvbjerg Allan , Magnusson Nils E.
Published: June 2014

Objective—

Neutrophil gelatinase-associated lipocalin (NGAL) is a glycoprotein stored in granules of neutrophil leukocytes participating in inflammatory and atherosclerotic processes and possibly plaque rupture. Despite the putative role of NGAL in atherosclerosis and acute myocardial infarction, human studies of plasma NGAL are still limited.

Approach and Results—

We prospectively followed 5599 randomly selected men and women from the community in the fourth Copenhagen Heart Study. Plasma NGAL was measured at study entry. Participants were followed for 10 years. During follow-up, 20% died (n=1120) and 15% (n=884) developed a major adverse cardiovascular event. Plasma NGAL associated strongly with all inflammatory markers (high-sensitivity C-reactive protein, total leukocyte count, neutrophil count) and inversely with estimated glomerular filtration rate (all,
P
<0.001). Multivariate analysis identified neutrophil leukocyte count as the main determinant of plasma NGAL. During follow-up, participants with increasing NGAL had increased risk of all-cause mortality and major adverse cardiovascular event (both,
P
<0.001). Even after adjustment for confounding risk factors by Cox regression analysis, NGAL remained an independent predictor of both all-cause mortality and major adverse cardiovascular event. When added to the Framingham risk score, NGAL improved
c
-statistics and correctly reclassified ≈15% into more appropriate risk groups. In comparison with high-sensitivity C-reactive protein, when both markers were added to the Framingham risk score, NGAL conferred 3× to 4× the risk.

Conclusions—

Plasma NGAL is strongly associated with inflammation in the general population. NGAL independently associated with 10-year outcome, and when added to the Framingham risk score, NGAL both improves
c
-statistics and correctly reclassifies participants into more accurate risk categories.
Diagnostic Value of Isoproterenol Testing in Arrhythmogenic Right Ventricular Cardiomyopathy
Authors: Denis Arnaud , Sacher Frédéric , Derval Nicolas , Lim Han. S. , Cochet Hubert , Shah Ashok J. , Daly Matthew , Pillois Xavier , Ramoul Khaled , Komatsu Yuki , Zemmoura Adlane , Amraoui Sana , Ritter Philippe , Ploux Sylvain , Bordachar Pierre , Hocini Mélèze , Jaïs Pierre , Haïssaguerre Michel
Published: June 2014

Background—

Although the Task Force Criteria for arrhythmogenic right ventricular cardiomyopathy (ARVC) have recently been updated, the diagnosis remains challenging in the early stages. The aim of this study was to evaluate the diagnostic value of β-adrenergic stimulation in ARVC.

Methods and Results—

We evaluated 412 consecutive patients (213 men, age 41.5±16 years) referred for premature ventricular contractions evaluation or suspected ARVC. Isoproterenol testing was performed with continuous infusion of isoproterenol (45 μg/min) for 3 minutes. It was considered positive if there were either (1) polymorphic premature ventricular contractions with ≥1 couplet or (2) sustained or nonsustained ventricular tachycardia with left bundle branch block excluding right ventricular outflow tract ventricular tachycardia. ARVC was diagnosed in 35 patients at initial evaluation (23 men, aged 42±15 years). Isoproterenol testing was positive in 32 of 35 (91.4%) patients with ARVC and in 42 of 377 (11.1%) patients without ARVC (
P
<0.0001). Sensitivity, specificity, positive, and negative predictive values of isoproterenol testing to diagnose ARVC were 91.4%, 88.9%, 43.2%, and 99.1%, respectively. During a mean follow-up period of 5.6±4.4 years, 6 additional patients met diagnostic criteria for ARVC. Importantly, initial isoproterenol testing was positive in 6 of 6 (100%) of these patients. Survival free from ARVC diagnosis was significantly lower in the positive isoproterenol group than in the negative isoproterenol group (
P
<0.0001, exact log-rank test).

Conclusions—

Ventricular arrhythmogenicity during isoproterenol testing is highly sensitive (sensitivity, 91.4%) for the diagnosis of ARVC, particularly in its early stages.
Role of Right Ventricle and Dynamic Pulmonary Hypertension on Determining ΔVO
2
/ΔWork Rate Flattening
Authors: Bandera Francesco , Generati Greta , Pellegrino Marta , Donghi Valeria , Alfonzetti Eleonora , Gaeta Maddalena , Villani Simona , Guazzi Marco
Published: June 2014

Background—

Several cardiovascular diseases are characterized by an impaired O
2
kinetic during exercise. The lack of a linear increase of Δoxygen consumption (V
O
2
)/ΔWork Rate (WR) relationship, as assessed by expired gas analysis, is considered an indicator of abnormal cardiovascular efficiency. We aimed at describing the frequency of ΔVO
2
/ΔWR flattening in a symptomatic population of cardiac patients, characterizing its functional profile, and testing the hypothesis that dynamic pulmonary hypertension and right ventricular contractile reserve play a major role as cardiac determinants.

Methods and Results—

We studied 136 patients, with different cardiovascular diseases, referred for exertional dyspnoea. Cardiopulmonary exercise test combined with simultaneous exercise echocardiography was performed using a symptom-limited protocol. ΔVO
2
/ΔWR flattening was observed in 36 patients (group A, 26.5% of population) and was associated with a globally worse functional profile (reduced peak V
O
2
, anaerobic threshold, O
2
pulse, impaired VE/VCO
2
). At univariate analysis, exercise ejection fraction, exercise mitral regurgitation, rest and exercise tricuspid annular plane systolic excursion, exercise systolic pulmonary artery pressure, and exercise cardiac output were all significantly (
P
<0.05) impaired in group A. The multivariate analysis identified exercise systolic pulmonary artery pressure (odds ratio, 1.06; confidence interval, 1.01–1.11;
P
=0.01) and exercise tricuspid annular plane systolic excursion (odds ratio, 0.88; confidence interval, 0.80–0.97;
P
=0.01) as main cardiac determinants of ΔVO
2
/ΔWR flattening; female sex was strongly associated (odds ratio, 6.10; confidence interval, 2.11–17.7;
P
<0.01).

Conclusions—

In patients symptomatic for dyspnea, the occurrence of ΔVO
2
/ΔWR flattening reflects a significantly impaired functional phenotype whose main cardiac determinants are the excessive systolic pulmonary artery pressure increase and the reduced peak right ventricular longitudinal systolic function.
Predicting the Risk of Venous Thromboembolism in Patients Hospitalized With Heart Failure
Authors: Mebazaa Alexandre , Spiro Theodore E. , Büller Harry R. , Haskell Lloyd , Hu Dayi , Hull Russell , Merli Geno , Schellong Sebastian W. , Spyropoulos Alex C. , Tapson Victor F. , De Sanctis Yoriko , Cohen Alexander T.
Published: June 2014

Background—

Whether heart failure (HF) increases the risk of venous thromboembolism (VTE) is not well established. In the phase III MAGELLAN (Multicenter, rAndomized, parallel Group Efficacy and safety study for the prevention of venous thromboembolism in hospitalized medically iLL patients comparing rivaroxabAN with enoxaparin) trial, extended-duration rivaroxaban was compared with standard-duration enoxaparin followed by placebo for VTE prevention in 8101 hospitalized acutely ill patients with or without HF. The aim of this analysis was to evaluate the relationship between HF severity and the risk of VTE in MAGELLAN patients.

Methods and Results—

Hospitalized patients diagnosed with HF were included according to New York Heart Association class III or IV at admission (n=2593). HF severity was determined by N-terminal probrain natriuretic peptide (NT-proBNP) plasma concentrations (median 1904 pg/mL). Baseline plasma D-dimer concentrations ranged from 0.6 to 1.7 μg/L for the less and more severe HF subgroups. Patients with more severe HF had a greater incidence of VTE versus patients with less severe HF, with a significant trend up to Day 10 (4.3% versus 2.2%;
P
=0.0108) and Day 35 (7.2% versus 4.1%;
P
=0.0150). Multivariable analysis confirmed that NT-proBNP concentration was associated with VTE risk up to Day 10 (
P
=0.017) and D-dimer concentration with VTE risk up to Day 35 (
P
=0.005). The association between VTE risk and HF severity that was observed in the enoxaparin/placebo group was not seen in the extended-duration rivaroxaban group.

Conclusions—

Patients with more severe HF, as defined by high NT-proBNP plasma concentration, were at increased risk of VTE. NT-proBNP may be useful to identify high short-term risk, whereas elevated D-dimer may be suggestive of high midterm risk.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00571649.
Morphological revision of the genus Aiptasia and the family Aiptasiidae (Cnidaria, Actiniaria, Metridioidea)
Authors: GRAJALES ALEJANDRO , RODRÍGUEZ ESTEFANÍA
Published: June 2014

Sea anemones of the genus Aiptasia Gosse, 1858 are conspicuous members of shallow-water environments worldwide and serve as a model system for studies of cnidarian-dinoflagellate symbiosis. However, to date there have been no comprehensive analyses investigating the systematics of the group. In addition, previously published phylogenetic studies of sea anemones have shown that the genus is not monophyletic. Herein we revise the genus Aiptasia and the family Aiptasiidae Carlgren, 1924 using newly-collected material. We find that the formerly-named A. pallida (Agassiz in Verrill, 1864) (now Exaiptasia pallida comb. nov.) encompasses a single, widespread species from the tropics and subtropics; we erect a new genus, Exaiptasia gen. nov., for this species primarily based on cnidae, mode of asexual reproduction and symbionts. We also find morphological evidence that supports splitting A. mutabilis into two species: A. couchii (Cocks, 1851) and A. mutabilis. In addition, we find Bellactis Dube, 1983 (formerly placed within Sagartiidae Gosse, 1858) and Laviactis gen. nov. (formerly known Ragactis Andres, 1883, whose familial placement was previously uncertain) belonging within Aiptasiidae. Aiptasiidae is a morphologically homogeneous family whose members (those species in genera Aiptasia, Aiptasiogeton Schmidt, 1972, Bartholomea Duchassaing de Fombressin & Michelotti, 1864, Bellactis, Exaiptasia gen. nov., and Laviactis gen. nov.) are characterized by ectodermal longitudinal muscles in the distal column, rows of cinclides in mid-column, microbasic b-mastigophores in the column, and acontia with basitrichs and microbasic p-amastigophores.
PERSIANN-CDR: Daily Precipitation Climate Data Record from Multisatellite Observations for Hydrological and Climate Studies
Authors: Ashouri Hamed , Hsu Kuo-Lin , Sorooshian Soroosh , Braithwaite Dan K. , Knapp Kenneth R. , Cecil L. Dewayne , Nelson Brian R. , Prat Olivier P.
Published: June 2014

A new retrospective satellite-based precipitation dataset is constructed as a climate data record for hydrological and climate studies. Precipitation Estimation from Remotely Sensed Information using Artificial Neural Networks–Climate Data Record (PERSIANN-CDR) provides daily and 0.25° rainfall estimates for the latitude band 60°S–60°N for the period of 1 January 1983 to 31 December 2012 (delayed present). PERSIANN-CDR is aimed at addressing the need for a consistent, long-term, high-resolution, and global precipitation dataset for studying the changes and trends in daily precipitation, especially extreme precipitation events, due to climate change and natural variability. PERSIANN-CDR is generated from the PERSIANN algorithm using GridSat-B1 infrared data. It is adjusted using the Global Precipitation Climatology Project (GPCP) monthly product to maintain consistency of the two datasets at 2.5° monthly scale throughout the entire record. Three case studies for testing the efficacy of the dataset against available observations and satellite products are reported. The verification study over Hurricane Katrina (2005) shows that PERSIANN-CDR has good agreement with the stage IV radar data, noting that PERSIANN-CDR has more complete spatial coverage than the radar data. In addition, the comparison of PERSIANN-CDR against gauge observations during the 1986 Sydney flood in Australia reaffirms the capability of PERSIANN-CDR to provide reasonably accurate rainfall estimates. Moreover, the probability density function (PDF) of PERSIANN-CDR over the contiguous United States exhibits good agreement with the PDFs of the Climate Prediction Center (CPC) gridded gauge data and the Tropical Rainfall Measuring Mission (TRMM) Multi-Satellite Precipitation Analysis (TMPA) product. The results indicate high potential for using PERSIANN-CDR for long-term hydroclimate studies in regional and global scales.
Departures from Axisymmetric Balance Dynamics during Secondary Eyewall Formation
Authors: Abarca Sergio F. , Montgomery Michael T.
Published: June 2014

Departures from axisymmetric balance dynamics are quantified during a case of secondary eyewall formation. The case occurred in a three-dimensional mesoscale convection-permitting numerical simulation of a tropical cyclone, integrated from an initial weak mesoscale vortex in an idealized quiescent environment. The simulation exhibits a canonical eyewall replacement cycle. Departures from balance dynamics are quantified by comparing the azimuthally averaged secondary circulation and corresponding tangential wind tendencies of the mesoscale integration with those diagnosed as the axisymmetric balanced response of a vortex subject to diabatic and tangential momentum forcing. Balance dynamics is defined here, following the tropical cyclone literature, as those processes that maintain a vortex in axisymmetric thermal wind balance.

The dynamical and thermodynamical fields needed to characterize the background vortex for the Sawyer–Eliassen inversion are obtained by azimuthally averaging the relevant quantities in the mesoscale integration and by computing their corresponding balanced fields. Substantial differences between azimuthal averages and their homologous balance-derived fields are found in the boundary layer. These differences illustrate the inappropriateness of the balance assumption in this region of the vortex (where the secondary eyewall tangential wind maximum emerges). Although the balance model does broadly capture the sense of the forced transverse (overturning) circulation, the balance model is shown to significantly underestimate the inflow in the boundary layer. This difference translates to unexpected qualitative differences in the tangential wind tendency. The main finding is that balance dynamics does not capture the tangential wind spinup during the simulated secondary eyewall formation event.
Assessing the Relationship Between Pediatric Media Guidance and Media Use in American Families
Authors: Lapierre Matthew A. , Piotrowski Jessica Taylor , Linebarger Deborah L.
Published: June 2014

Objective. American parents were surveyed to isolate demographic factors that predict reliance on a pediatrician, the American Academy of Pediatrics (AAP), or both for media guidance. We then investigated whether reliance on these resources resulted in different media practices with children. Methods. A nationally representative survey was conducted (n = 1454). Parents were asked what medical professionals they relied on for advice and reported relevant home media practices related to their child. Results. In all, 29% reported relying on their pediatrician, 24.9% said that they relied on the AAP, and 14.9% of all parents said they relied on both. Those following the AAP’s media guidelines were more likely to prohibit bedroom television and to follow all guidelines. Conclusions. The relatively low reliance on the AAP and pediatricians for media guidance suggest that more outreach is necessary. However, parents who report relying on the AAP for advice are more likely to enact these recommendations.
Hagar and Ishmael: A Commentary
Authors: Cohen Aryeh
Published: June 2014

This essay offers a commentary on the short story of Hagar and Ishmael’s expulsion at the hands of Abraham (Gen 21:14–20). The commentary lays a claim on traditional interpretation but is not itself necessarily a traditional interpretation.
Quantitative Ultrasound Imaging for Monitoring In Situ High-Intensity Focused Ultrasound Exposure
Authors: Ghoshal Goutam , Kemmerer Jeremy P. , Karunakaran Chandra , Abuhabsah Rami , Miller Rita J. , Sarwate Sandhya , Oelze Michael L.
Published: June 2014

Quantitative ultrasound (QUS) imaging is hypothesized to map temperature elevations induced in tissue with high spatial and temporal resolution. To test this hypothesis, QUS techniques were examined to monitor high-intensity focused ultrasound (HIFU) exposure of tissue. In situ experiments were conducted on mammary adenocarcinoma tumors grown in rats and lesions were formed using a HIFU system. A thermocouple was inserted into the tumor to provide estimates of temperature at one location. Backscattered time-domain waveforms from the tissue during exposure were recorded using a clinical ultrasonic imaging system. Backscatter coefficients were estimated using a reference phantom technique. Two parameters were estimated from the backscatter coefficient (effective scatterer diameter (ESD) and effective acoustic concentration (EAC). The changes in the average parameters in the regions corresponding to the HIFU focus over time were correlated to the temperature readings from the thermocouple. The changes in the EAC parameter were consistently correlated to temperature during both heating and cooling of the tumors. The changes in the ESD did not have a consistent trend with temperature. The mean ESD and EAC before exposure were 120 ± 16 μm and 32 ± 3 dB/cm3, respectively, and changed to 144 ± 9 μm and 51 ± 7 dB/cm3, respectively, just before the last HIFU pulse was delivered to the tissue. After the tissue cooled down to 37°C, the mean ESD and EAC were 126 ± 8 μm and 35 ± 4 dB/cm3, respectively. Peak temperature in the range of 50-60°C was recorded by a thermocouple placed just behind the tumor. These results suggest that QUS techniques have the potential to be used for non-invasive monitoring of HIFU exposure.
Improving Health Outcomes and Value with Care Pathways: The Otolaryngologist's Role
Authors: Altman Kenneth W.
Published: June 2014

With a growing interest in value‐based health care, there is an emphasis on establishing best practice, measuring outcomes, and improving clinical efficiencies. Best practice is a challenging concept with our growing knowledge base, and clinical practice guidelines (CPGs) help establish an approach to prioritize care and reduce practice variation. New challenges are emerging with a larger population of insured patients and a mandate to coordinate care with a shared electronic health record, and these are coupled with a massive growth in computing power. Care pathways (also called critical or clinical pathways) structure the implementation of CPGs, stratify high‐risk patients, and provide the opportunity to achieve improved value. These are dynamic processes that are supervised by interdisciplinary teams and have the potential to evolve with new information gathered from each of the steps. As we emerge from single to group medical practices and hospitals to health systems, care pathways will be critically needed for optimal population management in health care.
Structural-acoustic coupling study of tyre-cavity resonance
Authors: Mohamed Zamri , Wang Xu , Jazar Reza
Published: June 2014

The tyre cavity resonance induced cabin noise has been a major unsolved customer complaint issue for a long time. A study of coupled tyre-cavity structural-acoustic system using impedance compact mobility matrix is presented in this paper. This method offers a better physical interpretation and numerical prediction about a coupled tyre-cavity system than previous models. It can calculate the sound pressure inside the tyre cavity as well as the tread wall vibration velocity at the same time. The analytical results have been verified by the results of the VAOne vibro-acoustic model. The VAOne software was also validated by the results from a case study of a rectangular box-cavity system in previous literature. From the analytical calculation, the tyre cavity coupling modal frequency is found to be split into two close resonance frequencies if the tyre structural natural frequency is close to the fluid cavity resonance frequency. The geometric coupling coefficient has been calculated using Matlab code. This study provides a better insight into the resonance coupling phenomenon of the tyre cavity to the tyre structure and its root causes. It demonstrates more clear physical meaning of the tyre cavity coupling model and its inherent characteristics than that from ‘black box’ finite element software. This develops a better understanding of the problem and its root causes facilitates effective solutions for the problem. Even though the study was conducted in a tyre-cavity system, the solution and methodology are applicable to other toroidal shape structural-acoustic systems.
Accountability School Reform in Comparative Perspective
Authors: DiGaetano Alan
Published: June 2014

School reform politics in England and the United States over the last quarter century has revolved largely around the question of performance-based accountability. Accountability school reform in both countries has entailed standardization of curricula and assessment and the spread in the use of market mechanisms in school governance. To explain how these accountability reforms have retooled local governing institutions in ways that have reduced their autonomy and lessened their capacity to administer local school systems, this article applies the analytical framework of urban governing cycles to a comparative study of school reform politics in Bristol, England, and Boston, Massachusetts.
Hegel and global politics: Communitarianism or cosmopolitanism?
Authors: Burns Tony
Published: June 2014

This article discusses Hegel’s views on global politics by relating them to the ‘communitarianism versus cosmopolitanism’ debate. I distinguish between three different theoretical positions and three different readings of Hegel, which I associate with the notions of ‘communitarianism’, ‘strong cosmopolitanism’ and ‘weak cosmopolitanism’, respectively. Contrary to a commonly held view that Hegel is not a cosmopolitan thinker at all, in any sense of the term, I argue that he is best thought of as a weak cosmopolitan thinker rather than a communitarian or a strong cosmopolitan advocate of the idea of a world-state. In passing, the article refers to the relationship which exists between Hegel’s ideas and those of three twentieth-century theorists who might be associated with these theoretical positions and these different readings of Hegel, namely, Carl Schmitt, Alexandre Kojève and Jürgen Habermas. The article also refers to the methodological problems which are confronted by readers of Hegel’s writings who wish to apply his ideas to the problems of global politics today. Here I refer to a distinction which I have made elsewhere between different kinds of reading, namely the interpretation, appropriation and the reconstruction of texts, which is especially relevant for readers of the works of Hegel.
Seeing the Math in the Story
Authors: Schley Dan R. , Fujita Kentaro
Published: June 2014

The negative social, health, financial, and other life outcomes associated with mathematical proficiency deficits highlight the need to understand the underlying cognitive operations entailed in solving math problems. We focus specifically on mathematical word problems and propose that abstraction can enhance performance by helping people see beyond the incidental details described in word problems and to recognize instead the underlying mathematical relationships. Three studies manipulated abstraction as a procedural mind-set (i.e., inducing abstraction in one task and observing its “carry-over” effect in subsequent unrelated tasks) and observed performance on both numeric and word problems. Participants in the abstract, relative to concrete, mind-set condition were more successful in translating word problems into their analogous numeric forms, resulting in improved performance. We discuss implications of these findings for understanding individual and group differences in mathematics proficiencies, which may stem from both chronic and situational factors, and for the development of novel interventions.
Perceptions of Special Education and Career and Technical Education Collaboration and Communication
Authors: Schmalzried Joan E. , Harvey Michael W.
Published: June 2014

This study explored perceptions of current practices used by secondary educators (special education teachers and guidance counselors) and stand-alone career and technical education (CTE) centers when working with students with disabilities from sending high schools participating in secondary CTE from one midwestern state. The study looked at perceptions held by each educational setting (high school and secondary CTE) regarding needs and responsibility when working with these shared students. Study participants were provided a paper-and-pencil survey consisting of Likert-type scale and forced choice questions. Results indicated inconsistencies in the methods used to share student information and who was responsible for providing that information. Many respondents did not feel regular communication took place between CTE and special education. The findings reinforce concerns represented in more than a decade of research in this area. Recommendations are made for how CTE and special education can better communicate and collaborate on behalf of students with disabilities in CTE.
The effect of multiple martensitic transformations on diffusion of Fe and Ni atoms in Fe-31.7%Ni-0.06%C alloy
Authors: Danilchenko Vitaliy E , Mazanko Vladimir F , Iakovlev Viktor E
Published: June 2014

Diffusion characteristics of iron and nickel atoms were investigated using radioactive isotopes method in phase-hardened metastable iron-nickel Fe-31.7%Ni-0.06%C alloy with nanofragmented structure. It has been found that diffusion mobility of nickel and iron atoms in reverted austenite of Fe-31.7%Ni-0.06%C alloy significantly increases as the result of multiple γ-α-γ martensitic transformations. The diffusion coefficients of nickel and iron in the austenite at 400°C corresponded to the stationary diffusion coefficients at the temperatures above 900°C. The revealed diffusion acceleration at low temperatures is caused by high-density dislocations and additional low-angle subboundaries of disoriented nanofragments of reverted austenite and deformation twin subboundaries formed during multiple γ-α-γ cycles.
Effect of ZnO:Cs2CO3 on the performance of organic photovoltaics
Authors: Kim Hyeong Pil , Yusoff Abd Rashid bin Mohd , Lee Hee Jae , Lee Seung Joo , Kim Hyo Min , Seo Gi Jun , Youn Jun Ho , Jang Jin
Published: June 2014

We demonstrate a new solution-processed electron transport layer (ETL), zinc oxide doped with cesium carbonate (ZnO:Cs2CO3), for achieving organic photovoltaics (OPVs) with good operational stability at ambient air. An OPV employing the ZnO:Cs2CO3 ETL exhibits a fill factor of 62%, an open circuit voltage of 0.90 V, and a short circuit current density of −6.14 mA/cm2 along with 3.43% power conversion efficiency. The device demonstrated air stability for a period over 4 weeks. In addition, we also studied the device structure dependence on the performance of organic photovoltaics. Thus, we conclude that ZnO:Cs2CO3 ETL could be employed in a suitable architecture to achieve high-performance OPV.
A mutation in a splicing factor that causes retinitis pigmentosa has a transcriptome-wide effect on mRNA splicing
Authors: Korir Paul K , Roberts Lisa , Ramesar Raj , Seoighe Cathal
Published: June 2014

Background

Substantial progress has been made in the identification of sequence elements that control mRNA splicing and the genetic variants in these elements that alter mRNA splicing (referred to as splicing quantitative trait loci – sQTLs). Genetic variants that affect mRNA splicing intransare harder to identify because their effects can be more subtle and diffuse, and the variants are not co-located with their targets. We carried out a transcriptome-wide analysis of the effects of a mutation in a ubiquitous splicing factor that causes retinitis pigmentosa (RP) on mRNA splicing, using exon microarrays.

Results

Exon microarray data was generated from whole blood samples obtained from four individuals with a mutation in the splicing factorPRPF8and four sibling controls. Although the mutation has no known phenotype in blood, there was evidence of widespread differences in splicing between cases and controls (affecting approximately 20% of exons). Most probesets with significantly different inclusion (defined as the expression intensity of the exon divided by the expression of the corresponding transcript) between cases and controls had higher inclusion in cases and corresponded to exons that were shorter than average, rich, located towards the 5’ end of the gene and flanked by long introns. Introns flanking affected probesets were particularly depleted for the shortest category of introns, associated with splicing via intron definition.

Conclusions

Our results show that a mutation in a splicing factor, with a phenotype that is restricted to retinal tissue, acts as atrans-sQTL cluster in whole blood samples. Characteristics of the affected exons suggest that they are spliced co-transcriptionally and via exon definition. However, due to the small sample size available for this study, further studies are required to confirm the widespread impact of thisPRPF8mutation on mRNA splicing outside the retina.
Diarrhea in young children from low-income countries leads to large-scale alterations in intestinal microbiota composition
Authors: Pop Mihai , Walker Alan W , Paulson Joseph , Lindsay Brianna , Antonio Martin , Hossain M Anowar , Oundo Joseph , Tamboura Boubou , Mai Volker , Astrovskaya Irina , Bravo Hector Corrada , Rance Richard , Stares Mark , Levine Myron M , Panchalingam Sandra , Kotloff Karen , Ikumapayi Usman N , Ebruke Chinelo , Adeyemi Mitchell , Ahmed Dilruba , Ahmed Firoz , Alam Meer Taifur , Amin Ruhul , Siddiqui Sabbir , Ochieng John B , Ouma Emmanuel , Juma Jane , Mailu Euince , Omore Richard , Morris J Glenn , Breiman Robert F , Saha Debasish , Parkhill Julian , Nataro James P , Stine O Colin
Published: June 2014

Background

Diarrheal diseases continue to contribute significantly to morbidity and mortality in infants and young children in developing countries. There is an urgent need to better understand the contributions of novel, potentially uncultured, diarrheal pathogens to severe diarrheal disease, as well as distortions in normal gut microbiota composition that might facilitate severe disease.

Results

We use high throughput 16S rRNA gene sequencing to compare fecal microbiota composition in children under five years of age who have been diagnosed with moderate to severe diarrhea (MSD) with the microbiota from diarrhea-free controls. Our study includes 992 children from four low-income countries in West and East Africa, and Southeast Asia. Known pathogens, as well as bacteria currently not considered as important diarrhea-causing pathogens, are positively associated with MSD, and these include Escherichia/Shigella, and Granulicatella species, and Streptococcus mitis/pneumoniae groups. In both cases and controls, there tend to be distinct negative correlations between facultative anaerobic lineages and obligate anaerobic lineages. Overall genus-level microbiota composition exhibit a shift in controls from low to high levels of Prevotella and in MSD cases from high to low levels of Escherichia/Shigella in younger versus older children; however, there was significant variation among many genera by both site and age.

Conclusions

Our findings expand the current understanding of microbiota-associated diarrhea pathogenicity in young children from developing countries. Our findings are necessarily based on correlative analyses and must be further validated through epidemiological and molecular techniques.
Characteristic bimodal profiles of RNA polymerase II at thousands of active mammalian promoters
Authors: Quinodoz Mathieu , Gobet Cédric , Naef Felix , Gustafson Kyle B
Published: June 2014

Background

In mammals, ChIP-seq studies of RNA polymerase II (PolII) occupancy have been performed to reveal how recruitment, initiation and pausing of PolII may control transcription rates, but the focus is rarely on obtaining finely resolved profiles that can portray the progression of PolII through sequential promoter states.

Results

Here, we analyze PolII binding profiles from high-coverage ChIP-seq on promoters of actively transcribed genes in mouse and humans. We show that the enrichment of PolII near transcription start sites exhibits a stereotypical bimodal structure, with one peak near active transcription start sites and a second peak 110 base pairs downstream from the first. Using an empirical model that reliably quantifies the spatial PolII signal, gene by gene, we show that the first PolII peak allows for refined positioning of transcription start sites, which is corroborated by mRNA sequencing. This bimodal signature is found both in mouse and humans. Analysis of the pausing-related factors NELF and DSIF suggests that the downstream peak reflects widespread pausing at the +1 nucleosome barrier. Several features of the bimodal pattern are correlated with sequence features such as CpG content and TATA boxes, as well as the histone mark H3K4me3.

Conclusions

We thus show how high coverage DNA sequencing experiments can reveal as-yet unnoticed bimodal spatial features of PolII accumulation that are frequent at individual mammalian genes and reminiscent of transcription initiation and pausing. The initiation-pausing hypothesis is corroborated by evidence from run-on sequencing and immunoprecipitation in other cell types and species.
Two new species of Begonia sect. Coelocentrum, B. guixiensis and B. longa, from Sino-Vietnamese limestone karsts
Authors: Peng Ching-I , Ku Shin-Ming , Yang Hsun-An , Leong Wai-Chao , Liu Yan , Nguyen Tien Hiep , Kono Yoshiko , Chung Kuo-Fang
Published: June 2014

Background

In our recent molecular phylogenetic study of Asian Begonia, two undescribed species, B. guixiensis sp. ined. (S. Guangxi, China) and B. longa sp. ined. (Vietnam), were sampled and placed within the strongly supported clade composed of Begonia sect. Coelocentrum and other co-distributed rhizomatous species in the Sino-Vietnamese limestone karsts. While Begonia sect. Coelocentrum has been recircumscribed based on the phylogenetic relationships, B. guixiensis sp. ined. and B. longa sp. ined. remain illegitimate names. In continuation of our studies in Asian Begonia, these two new species are described and illustrated.

Results

Begonia guixiensis resembles B. cylindrica in the peltate, subcoriaceous leaves, differing by the shape of ovary/fruit and the type of placentation. In aspect, B. longa bears a superficial resemblance to B. brevipedunculata in leaf shape in particular, differing by many other features such as the long internodes, shorter petioles and smaller leaves, longer peduncles and 3-locular ovary. The chromosome number of both new species is determined as 2n = 30.

Conclusion

A careful study of the literature, herbarium specimens and living plants, both in the wild and in cultivation in the experimental greenhouse, support the recognition of the two new species, which are described and illustrated herein.
Novel Pituitary Actions of TAC3 Gene Products in Fish Model: Receptor Specificity and Signal Transduction for Prolactin and Somatolactin α Regulation by Neurokinin B (NKB) and NKB-Related Peptide in Carp Pituitary Cells
Authors: Hu Guangfu , He Mulan , Ko Wendy K.W. , Lin Chengyuan , Wong Anderson O.L.
Published: June 2014

TAC3 is a member of tachykinins, and its gene product neurokinin B (NKB) has recently emerged as a key regulator for LH through modulation of kisspeptin/GnRH system within the hypothalamus. In fish models, TAC3 not only encodes NKB but also a novel tachykinin-like peptide called NKB-related peptide (NKBRP), and the pituitary actions of these TAC3 gene products are still unknown. Using grass carp as a model, the direct effects and postreceptor signaling for the 2 TAC3 products were examined at the pituitary level. Grass carp TAC3 was cloned and confirmed to encode NKB and NKBRP similar to that of other fish species. In carp pituitary cells, NKB and NKBRP treatment did not affect LH release and gene expression but up-regulated prolactin (PRL) and somatolactin (SL)α secretion, protein production, and transcript expression. The stimulation by these 2 TAC3 gene products on PRL and SLα release and mRNA levels were mediated by pituitary NK2 and NK3 receptors, respectively. Apparently, NKB- and NKBRP-induced SLα secretion and transcript expression were caused by adenylate cyclase/cAMP/protein kinase A, phospholipase C/inositol 1,4,5-triphosphate/protein kinase C and Ca2+/calmodulin/Ca2+/calmodulin-dependent protein kinase II activation. The signal transduction for the corresponding responses on PRL release and mRNA expression were also similar, except that the protein kinase C component was not involved. These findings suggest that the 2 TAC3 gene products do not play a role in LH regulation at the pituitary level in carp species but may serve as novel stimulators for PRL and SLα synthesis and secretion via overlapping postreceptor signaling mechanisms coupled to NK2 and NK3 receptors, respectively.
Angiotensin II Type 2 Receptor Stimulation Improves Fatty Acid Ovarian Uptake and Hyperandrogenemia in an Obese Rat Model of Polycystic Ovary Syndrome
Authors: Leblanc Samuel , Battista Marie-Claude , Noll Christophe , Hallberg Anders , Gallo-Payet Nicole , Carpentier André C. , Vine Donna F. , Baillargeon Jean-Patrice
Published: June 2014

Polycystic ovary syndrome (PCOS) is mainly defined by hyperandrogenism but is also characterized by insulin resistance (IR). Studies showed that overexposure of nonadipose tissues to nonesterified fatty acids (NEFA) may explain both IR and hyperandrogenism. Recent studies indicate that treatment with an angiotensin II type 2 receptor (AT2R)-selective agonist improves diet-induced IR. We thus hypothesized that PCOS hyperandrogenism is triggered by ovarian NEFA overexposure and is improved after treatment with an AT2R agonist. Experiments were conducted in 12-week-old female JCR:LA-cp/cp rats, which are characterized by visceral obesity, IR, hyperandrogenism, and polycystic ovaries. Control JCR:LA +/? rats have a normal phenotype. Rats were treated for 8 days with saline or the selective AT2R agonist C21/M24 and then assessed for: 1) fasting testosterone, NEFA, and insulin levels; and 2) an iv 14(R,S)-[18F]fluoro-6-thia-heptadecanoic acid test to determine NEFA ovarian tissue uptake (Km). Compared with controls, saline-treated PCOS/cp rats displayed higher insulin (100 vs 5.6 μU/mL), testosterone (0.12 vs 0.04 nmol/L), NEFA (0.98 vs 0.48 mmol/L), and Km (20.7 vs 12.9 nmol/g·min) (all P < .0001). In PCOS/cp rats, C21/M24 did not significantly improve insulin or NEFA but normalized testosterone (P = .004) and Km (P = .009), which were strongly correlated together in all PCOS/cp rats (ρ = 0.74, P = .009). In conclusion, in an obese PCOS rat model, ovarian NEFA uptake and testosterone levels are strongly associated and are both significantly reduced after short-term C21/M24 therapy. These findings provide new information on the role of NEFA in PCOS hyperandrogenemia and suggest a potential role for AT2R agonists in the treatment of PCOS.
ROS1 Signaling Regulates Epithelial Differentiation in the Epididymis
Authors: Jun Hyun Jung , Roy Jeremy , Smith Tegan B. , Wood Levi B. , Lane Keara , Woolfenden Steve , Punko Diana , Bronson Roderick T. , Haigis Kevin M. , Breton Sylvie , Charest Al
Published: June 2014

The initial segment (IS) of the epididymis plays an essential role in male fertility. The IS epithelium is undifferentiated and nonfunctional at birth. Prior to puberty, the epithelium undergoes differentiation that leads to the formation of a fully functional organ. However, the mechanistic details of this program are not well understood. To explore this further, we used genetic engineering to create a kinase dead allele of the ROS1 receptor tyrosine kinase in mice and studied the effects of ROS1 tyrosine kinase activity on the differentiation of the IS epithelium. We show that the expression and activation of ROS1 coincides with the onset of differentiation and is exclusively located in the IS of the maturing and adult mouse epididymides. Here we demonstrate that the differentiation of the IS is dependent on the kinase activity of ROS1 and its downstream effector MEK1/2-ERK1/2 signaling axis. Using genetic engineering, we show that germ line ablation of ROS1 kinase activity leads to a failure of the IS epithelium to differentiate, and as a consequence sperm maturation and infertility were dramatically perturbed. Pharmacological inhibition of ROS1 kinase activity in the developing epididymis, however, only delayed differentiation transiently and did not result in infertility. Our results demonstrate that ROS1 kinase activity and the ensuing MEK1/2-ERK1/2 signaling are necessary for the postnatal development of the IS epithelium and that a sustained ablation of ROS1 kinase activity within the critical window of terminal differentiation abrogate the function of the epididymis and leads to sterility.
mRNA-Seq Reveals Novel Molecular Mechanisms and a Robust Fingerprint in Graves' Disease
Authors: Yin Xiaoming , Sachidanandam Ravi , Morshed Syed , Latif Rauf , Shi Ruijin , Davies Terry F.
Published: June 2014

Context:

The immune response in autoimmune thyroid disease has been shown to occur primarily within the thyroid gland in which the most abundant antigens can be found. A variety of capture molecules are known to be expressed by thyroid epithelial cells and serve to attract and help retain an intrathyroidal immune infiltrate.

Objective:

To explore the entire repertoire of expressed genes in human thyroid tissue, we have deep sequenced the transcriptome (referred to as mRNA-Seq).

Design and Patients:

We applied mRNA-Seq to thyroid tissue from nine patients with Graves' disease subjected to total thyroidectomy and compared the data with 12 samples of normal thyroid tissue obtained from patients having a thyroid nodule removed. The expression for each gene was calculated from the sequencing data by taking the median of the coverage across the length of the gene. The expression levels were quantile normalized and a gene signature was derived from these.

Results:

On comparison of expression levels in tissues derived from Graves' patients and controls, there was clear evidence for overexpression of the antigen presentation pathway consisting of HLA and associated genes. We also found a robust disease signature and discovered active innate and adaptive immune signaling networks.

Conclusions:

These data reveal an active immune defense system in Graves' disease, which involves novel molecular mechanisms in its pathogenesis and development.
Transient infection of the zebrafish notochord with E. coli induces chronic inflammation
Authors: Nguyen-Chi Mai , Phan Quang Tien , Gonzalez Catherine , Dubremetz Jean-François , Levraud Jean-Pierre , Lutfalla Georges
Published: June 2014

Zebrafish embryos and larvae are now well-established models in which to study infectious diseases. Infections with non-pathogenic Gram-negative Escherichia coli induce a strong and reproducible inflammatory response. Here, we study the cellular response of zebrafish larvae when E. coli bacteria are injected into the notochord and describe the effects. First, we provide direct evidence that the notochord is a unique organ that is inaccessible to leukocytes (macrophages and neutrophils) during the early stages of inflammation. Second, we show that notochord infection induces a host response that is characterised by rapid clearance of the bacteria, strong leukocyte recruitment around the notochord and prolonged inflammation that lasts several days after bacteria clearance. During this inflammatory response, il1b is first expressed in macrophages and subsequently at high levels in neutrophils. Moreover, knock down of il1b alters the recruitment of neutrophils to the notochord, demonstrating the important role of this cytokine in the maintenance of inflammation in the notochord. Eventually, infection of the notochord induces severe defects of the notochord that correlate with neutrophil degranulation occurring around this tissue. This is the first in vivo evidence that neutrophils can degranulate in the absence of a direct encounter with a pathogen. Persistent inflammation, neutrophil infiltration and restructuring of the extracellular matrix are defects that resemble those seen in bone infection and in some chondropathies. As the notochord is a transient embryonic structure that is closely related to cartilage and bone and that contributes to vertebral column formation, we propose infection of the notochord in zebrafish larvae as a new model to study the cellular and molecular mechanisms underlying cartilage and bone inflammation.
Zebrafish as a model to assess cancer heterogeneity, progression and relapse
Authors: Blackburn Jessica S. , Langenau David M.
Published: June 2014

Clonal evolution is the process by which genetic and epigenetic diversity is created within malignant tumor cells. This process culminates in a heterogeneous tumor, consisting of multiple subpopulations of cancer cells that often do not contain the same underlying mutations. Continuous selective pressure permits outgrowth of clones that harbor lesions that are capable of enhancing disease progression, including those that contribute to therapy resistance, metastasis and relapse. Clonal evolution and the resulting intratumoral heterogeneity pose a substantial challenge to biomarker identification, personalized cancer therapies and the discovery of underlying driver mutations in cancer. The purpose of this Review is to highlight the unique strengths of zebrafish cancer models in assessing the roles that intratumoral heterogeneity and clonal evolution play in cancer, including transgenesis, imaging technologies, high-throughput cell transplantation approaches and in vivo single-cell functional assays.
Repairing quite swimmingly: advances in regenerative medicine using zebrafish
Authors: Goessling Wolfram , North Trista E.
Published: June 2014

Regenerative medicine has the promise to alleviate morbidity and mortality caused by organ dysfunction, longstanding injury and trauma. Although regenerative approaches for a few diseases have been highly successful, some organs either do not regenerate well or have no current treatment approach to harness their intrinsic regenerative potential. In this Review, we describe the modeling of human disease and tissue repair in zebrafish, through the discovery of disease-causing genes using classical forward-genetic screens and by modulating clinically relevant phenotypes through chemical genetic screening approaches. Furthermore, we present an overview of those organ systems that regenerate well in zebrafish in contrast to mammalian tissue, as well as those organs in which the regenerative potential is conserved from fish to mammals, enabling drug discovery in preclinical disease-relevant models. We provide two examples from our own work in which the clinical translation of zebrafish findings is either imminent or has already proven successful. The promising results in multiple organs suggest that further insight into regenerative mechanisms and novel clinically relevant therapeutic approaches will emerge from zebrafish research in the future.