bluuebunny/crossref_metadata_2025 huggingface dataset:
Consistent inter-protocol differences in resting-state functional connectomes between normal aging and mild cognitive impairment
Authors: Tam Angela , Dansereau Christian , Badhwar AmanPreet , Orban Pierre , Belleville Sylvie , Chertkow Howard , Dagher Alain , Hanganu Alexandru , Monchi Oury , Rosa-Neto Pedro , Shmuel Amir , Wang Seqian , Breitner John , Bellec Pierre ,   Alzheimer’s Disease Neuroimaging Initiative
Published: May 2015

Resting-state functional connectivity is a promising biomarker for Alzheimer’s disease. However, previous resting-state functional magnetic resonance imaging studies in Alzheimer’s disease and mild cognitive impairment (MCI) have shown limited reproducibility as they have had small sample sizes and substantial variation in study protocol. We sought to identify functional brain networks and connections that could consistently discriminate normal aging from MCI despite variations in scanner manufacturer, imaging protocol, and diagnostic procedure. We therefore pooled four independent datasets, including 112 healthy controls and 143 patients with MCI, systematically testing multiple brain connections for consistent differences. The largest effects associated with MCI involved the ventromedial and dorsomedial prefrontal cortex, striatum, and middle temporal lobe. Compared with controls, patients with MCI exhibited significantly decreased connectivity within the frontal lobe, between frontal and temporal areas, and between regions of the cortico-striatal-thalamic loop. Despite the heterogeneity of methods among the four datasets, we identified robust MCI-related connectivity changes with small to medium effect sizes and sample size estimates recommending a minimum of 150 to 400 total subjects to achieve adequate statistical power. If our findings can be replicated and associated with other established biomarkers of Alzheimer’s disease (e.g. amyloid and tau quantification), then these functional connections may be promising candidate biomarkers for Alzheimer’s disease.
Endless Forms Most Beau-toe-ful: Evolution of the Human Hallux
Authors: Throckmorton Zachary
Published: May 2015

Background

The adduction of the first pedal ray in humans, such that the hallux is incapable of functional opposability, is a major feature of the evolution of the hominin foot (e.g. Darwin 1872, Haeckel 1879, Latimer and Lovejoy 1990). While hallucal adduction facilitates obligate bipedalism, it inhibits but does not eliminate arboreal grasping ability. The angle of the hallux (as determined by the longitudinal axis of the first metatarsal) relative to the rest of the foot (as determined by the longitudinal axis of the second metatarsal) is a product of both hard-and soft-tissues. Given the failure of soft tissue to fossilize, direct evidence for hallucal angle evolution is scanty, and consensus has not emerged as to when and how the modern human condition of hallucal non-opposability evolved.

Methodology/Principal Findings

Analysis of a large sample (n = 331) of radiographs taken from the dorsal aspect of living human feet elucidates the relationship between osteological measures and the magnitude of hallucal adduction, which is resultant of both hard-and soft-tissue anatomy (Lovejoyet al.2009). I describe the correlation of hallucal convergence with first metatarsal posterior articular facet morphology, which allows inference of hallucal convergence in the absence of the medial cuneiform. I report parameters of modern human hallucal convergence variation and offer insight into the hominin fossil record. I infer that the hallucal convergence of the recently reported specimen from Burtele (BRT-VP-2/73) falls within the range of living human variation, inconsistent with the interpretation that this hominin retained the ability to oppose its great toe for the purpose of arboreal locomotion (Haile-Selassieet al. 2012). Of the fossil hominin first metatarsals surveyed, all fall within the range of living human variation, consistent with previous research on medial cuneiform (McHenry and Jones 2006) and first metatarsal (Berillon 1999) morphology.

Conclusions/Significance

This study finds that the modern human condition of hallucal non-opposability was present in the genusAustralopithecus. However, while the Burtele specimen (BRT-VP-2/73) falls within the range of living human variation, it displays a markedly divergent hallux compared to most living humans. This study suggests that, as in humans today, there was variation in hallucal divergence in Plio-Pleistocene hominins. Rather than using the terms ‘opposability’ and the ambiguously synonymous ‘grasping,’ I suggest here the term ‘clamping’ (as in the motion performed by a clamp) be used to describe the less powerful and less dexterous ability of modern humans to place and hold a thin, narrow object between the great toe and second toe ray in a limited, albeit functional, manner.
A Perspective on Interaction Tests in Genetic Association Studies
Authors: Aschard Hugues
Published: May 2015

The identification of gene-gene and gene-environment interaction in human traits and diseases is an active area of research that generates high expectation, and most often lead to high disappointment. This is partly explained by a misunderstanding of some of the inherent characteristics of interaction effects. Here, I untangle several theoretical aspects of standard regression-based interaction tests in genetic association studies. In particular, I discuss variables coding scheme, interpretation of effect estimate, power, and estimation of variance explained in regard of various hypothetical interaction patterns. I show first that the simplest biological interaction models—in which the magnitude of a genetic effect depends on a common exposure—are among the most difficult to identify. Then, I demonstrate the demerits of the current strategy to evaluate the contribution of interaction effects to the variance of quantitative outcomes and argue for the use of new approaches to overcome these issues. Finally I explore the advantages and limitations of multivariate models when testing for interaction between multiple SNPs and/or multiple exposures, using either a joint test, or a test of interaction based on risk score. Theoretical and simulated examples presented along the manuscript demonstrate that the application of these methods can provide a new perspective on the role of interaction in multifactorial traits.
The effects of time-varying temperature on delays in genetic networks
Authors: Gomez Marcella M. , Murray Richard M. , Bennett Matthew R.
Published: May 2015

Delays in gene networks result from the sequential nature of protein assembly. However, it is unclear how models of gene networks that use delays should be modified when considering time-dependent changes in temperature. This is important, as delay is often used in models of genetic oscillators that can be entrained by periodic fluctuations in temperature. Here, we analytically derive the time dependence of delay distributions in response to time-varying temperature changes. We find that the resulting time-varying delay is nonlinearly dependent on parameters of the time-varying temperature such as amplitude and frequency, therefore, applying an Arrhenius scaling may result in erroneous conclusions. We use these results to examine a model of a synthetic gene oscillator with temperature compensation. We show that temperature entrainment follows from the same mechanism that results in temperature compensation. Under a common Arrhenius scaling alone, the frequency of the oscillator is sensitive to changes in the mean temperature but robust to changes in the frequency of a periodically time-varying temperature. When a mechanism for temperature compensation is included in the model, however, we show that the oscillator is entrained by periodically varying temperature even when maintaining insensitivity to the mean temperature.
Distance from Sub-Saharan Africa Predicts Mutational Load in Diverse Human Genomes
Authors: Henn Brenna M. , Botigué Laura R. , Peischl Stephan , Dupanloup Isabelle , Lipatov Mikhail , Maples Brian K. , Martin Alicia R. , Musharoff Shaila , Cann Howard , Snyder Michael , Excoffier Laurent , Kidd Jeffrey M. , Bustamante Carlos D.
Published: May 2015

The Out-of-Africa (OOA) dispersal ~50,000 years ago is characterized by a series of founder events as modern humans expanded into multiple continents. Population genetics theory predicts an increase of mutational load in populations undergoing serial founder effects during range expansions. To test this hypothesis, we have sequenced full genomes and high-coverage exomes from 7 geographically divergent human populations from Namibia, Congo, Algeria, Pakistan, Cambodia, Siberia and Mexico. We find that individual genomes vary modestly in the overall number of predicted deleterious alleles. We show via spatially explicit simulations that the observed distribution of deleterious allele frequencies is consistent with the OOA dispersal, particularly under a model where deleterious mutations are recessive. We conclude that there is a strong signal of purifying selection at conserved genomic positions within Africa, but that many predicted deleterious mutations have evolved as if they were neutral during the expansion out of Africa. Under a model where selection is inversely related to dominance, we show that OOA populations are likely to have a higher mutation load due to increased allele frequencies of nearly neutral variants that are recessive or partially recessive.
Genomic epidemiology of the current wave of artemisinin resistant malaria
Authors: Amato Roberto , Miotto Olivo , Woodrow Charles , Almagro-Garcia Jacob , Sinha Ipsita , Campino Susana , Mead Daniel , Drury Eleanor , Kekre Mihir , Sanders Mandy , Amambua-Ngwa Alfred , Amaratunga Chanaki , Amenga-Etego Lucas , Anderson Tim J C , Andrianaranjaka Voahangy , Apinjoh Tobias , Ashley Elizabeth , Auburn Sarah , Awandare Gordon A , Baraka Vito , Barry Alyssa , Boni Maciej F , Borrmann Steffen , Bousema Teun , Branch Oralee , Bull Peter C , Chotivanich Kesinee , Conway David J , Craig Alister , Day Nicholas P , Djimdé Abdoulaye , Dolecek Christiane , Dondorp Arjen M , Drakeley Chris , Duffy Patrick , Echeverri-Garcia Diego F , Egwang Thomas G , Fairhurst Rick M , Faiz Abul , Fanello Caterina I , Hien Tran Tinh , Hodgson Abraham , Imwong Mallika , Ishengoma Deus , Lim Pharath , Lon Chanthap , Marfurt Jutta , Marsh Kevin , Mayxay Mayfong , Mobegi Victor , Mokuolu Olugbenga , Montgomery Jacqui , Mueller Ivo , Kyaw Myat Phone , Newton Paul N , Nosten Francois , Noviyanti Rintis , Nzila Alexis , Ocholla Harold , Oduro Abraham , Onyamboko Marie , Ouedraogo Jean-Bosco , Phyo Aung Pyae , Plowe Christopher V , Price Ric N , Pukrittayakamee Sasithon , Randrianarivelojosia Milijaona , Ringwald Pascal , Ruiz Lastenia , Saunders David , Shayo Alex , Siba Peter , Takala-Harrison Shannon , Thanh Thuy-Nhien Nguyen , Thathy Vandana , Verra Federica , White Nicholas J , Htut Ye , Cornelius Victoria J , Giacomantonio Rachel , Muddyman Dawn , Henrichs Christa , Malangone Cinzia , Jyothi Dushyanth , Pearson Richard D , Rayner Julian C , McVean Gilean , Rockett Kirk , Miles Alistair , Vauterin Paul , Jeffery Ben , Manske Magnus , Stalker Jim , MacInnis Bronwyn , Kwiatkowski Dominic P ,   MalariaGEN Plasmodium falciparum Community Project
Published: May 2015

Artemisinin resistantPlasmodium falciparumis advancing across Southeast Asia in a soft selective sweep involving at least 20 independentkelch13mutations. In a large global survey, we find thatkelch13mutations which cause resistance in Southeast Asia are present at low frequency in Africa. We show that Africankelch13mutations have originated locally, and thatkelch13shows a normal variation pattern relative to other genes in Africa, whereas in Southeast Asia there is a great excess of non-synonymous mutations, many of which cause radical amino-acid changes. Thus,kelch13is not currently undergoing strong selection in Africa, despite a deep reservoir of standing variation that could potentially allow resistance to emerge rapidly. The practical implications are that public health surveillance for artemisinin resistance should not rely onkelch13data alone, and interventions to prevent resistance must account for local evolutionary conditions, shown by genomic epidemiology to differ greatly between geographical regions.
Determining Exon Connectivity in Complex mRNAs by Nanopore Sequencing
Authors: Bolisetty Mohan T. , Rajadinakaran Gopinath , Graveley Brenton R.
Published: May 2015

Though powerful, short-read high throughput RNA sequencing is limited in its ability to directly measure exon connectivity in mRNAs containing multiple alternative exons located farther apart than the maximum read lengths. Here, we use the Oxford Nanopore MinION™sequencer to identify 7,899 ‘full-length’ isoforms expressed from fourDrosophilagenes,Dscam1,MRP,Mhc, andRdl. These results demonstrate that nanopore sequencing can be used to deconvolute individual isoforms and that it has the potential to be an important method for comprehensive transcriptome characterization.
Regulation of Jasmonate-Mediated Stamen Development and Seed Production by a bHLH-MYB Complex in Arabidopsis
Authors: Qi Tiancong , Huang Huang , Song Susheng , Xie Daoxin
Published: May 2015

Stamens are the plant male reproductive organs essential for plant fertility. Proper development of stamens is modulated by environmental cues and endogenous hormone signals. Deficiencies in biosynthesis or perception of the phytohormone jasmonate (JA) attenuate stamen development, disrupt male fertility, and abolish seed production in Arabidopsis thaliana. This study revealed that JA-mediated stamen development and seed production are regulated by a bHLH-MYB complex. The IIIe basic helix-loop-helix (bHLH) transcription factor MYC5 acts as a target of JAZ repressors to function redundantly with other IIIe bHLH factors such as MYC2, MYC3, and MYC4 in the regulation of stamen development and seed production. The myc2 myc3 myc4 myc5 quadruple mutant exhibits obvious defects in stamen development and significant reduction in seed production. Moreover, these IIIe bHLH factors interact with the MYB transcription factors MYB21 and MYB24 to form a bHLH-MYB transcription complex and cooperatively regulate stamen development. We speculate that the JAZ proteins repress the bHLH-MYB complex to suppress stamen development and seed production, while JA induces JAZ degradation and releases the bHLH-MYB complex to subsequently activate the expression of downstream genes essential for stamen development and seed production.
The Arabidopsis R-SNARE VAMP721 Interacts with KAT1 and KC1 K+ Channels to Moderate K+ Current at the Plasma Membrane
Authors: Zhang Ben , Karnik Rucha , Wang Yizhou , Wallmeroth Niklas , Blatt Michael R. , Grefen Christopher
Published: May 2015

SNARE (soluble N-ethylmaleimide-sensitive factor protein attachment protein receptor) proteins drive vesicle traffic, delivering membrane and cargo to target sites within the cell and at its surface. They contribute to cell homeostasis, morphogenesis, and pathogen defense. A subset of SNAREs, including the Arabidopsis thaliana SNARE SYP121, are known also to coordinate solute uptake via physical interactions with K+ channels and to moderate their gating at the plasma membrane. Here, we identify a second subset of SNAREs that interact to control these K+ channels, but with opposing actions on gating. We show that VAMPs (vesicle-associated membrane proteins), which target vesicles to the plasma membrane, also interact with and suppress the activities of the inward-rectifying K+ channels KAT1 and KC1. Interactions were evident in yeast split-ubiquitin assays, they were recovered in vivo by ratiometric bimolecular fluorescence complementation, and they were sensitive to mutation of a single residue, Tyr-57, within the longin domain of VAMP721. Interaction was also recovered on exchange of the residue at this site in the homolog VAMP723, which normally localizes to the endoplasmic reticulum and otherwise did not interact. Functional analysis showed reduced channel activity and alterations in voltage sensitivity that are best explained by a physical interaction with the channel gates. These actions complement those of SYP121, a cognate SNARE partner of VAMP721, and lead us to propose that the channel interactions reflect a “hand-off” in channel control between the two SNARE proteins that is woven together with vesicle fusion.
Pathogenesis and association of Mycoplasma pneumoniae infection with cardiac and hepatic damage
Authors: Fan Qing , Meng Jun , Li Peijie , Liu Zhigang , Sun Ying , Yan Ping
Published: May 2015

The aim of this study was to investigate the pathogenesis of Mycoplasma pneumoniae (MP) infection and its association with cardiac and hepatic damage. Between March 2013 and March 2014, 59 children with MP pneumonia (MPP) and 30 healthy children were enrolled. Serum titers of TLR4, T cell immunoglobulin and mucin‐domain (TIM) 3, IL‐10, TNF‐α, and IFN‐γ were measured both in children with MPP and healthy children. Additionally, MP‐specific antibody titer and creatine kinase‐MB (CK‐MB), and alanine transaminase (ALT) titers were measured in patients with MPP. There were significant differences between the MPP patients and healthy controls in titers of TIM1 (P < 0.01), TLR2 (P = 0.028), TLR4 (P = 0.019), IL‐10 (P < 0.01), TNF‐α (P < 0.01) and IFN‐γ (P < 0.01); however, no significant difference was found in TIM3 titers (P = 0.8181). TIM1 was correlated with CK‐MB (P = 0.025), whereas both TIM1 and TLR2 titers were correlated with MP‐specific antibody titers (P < 0.001; P = 0.003, respectively). Additionally, there were correlations between ALT, TIM3, and TLR2 titers (P = 0.025; P = 0.037, respectively). The titers of TIM1 were significantly higher in patients with cardiac damage (P = 0.007) than in those without it, whereas the titers of TLR2 were significantly higher in patients with hepatic damage (P = 0.026) than in those without it. TLR2, TLR4 and TIM1 may be involved in the process of MP infection. Additionally, TLR2, TLR4, TIM1 and TIM3 may play particular roles in the pathogenesis of MPP‐associated cardiac and hepatic damage.
Capturing Key NANDA‐I Nursing Diagnoses From Actual Clinical Data for Patients With Heart Failure
Authors: Park Hyejin , Tucker Denise A.
Published: May 2015

Purpose

The purpose of the study was to identify key nursing diagnoses with related factors and signs/symptoms using NANDA‐I for patients with heart failure (HF).

Methods

A retrospective descriptive design was used to address the research questions. Data were obtained from the records of patients discharged for 1 year with the medical diagnoses of HF from a Midwestern community hospital. A total of 272 inpatient records were analyzed to describe the frequency and percentage of NANDA‐I diagnosis with related factors and signs/symptoms.

Results

The top 10 NANDA‐I diagnoses associated with related factors and signs/symptoms were identified.

Conclusion

Further research related to standardized nursing terminologies such as NANDA‐I using large clinical databases from health information systems is needed to support evidence‐based nursing diagnosis decision making.
Respiratory Nursing Diagnoses: Presenting Evidence for Identification of the Defining Characteristics in Neonatal and Pediatric Populations
Authors: Avena Marta J. , da Luz Gonçalves Pedreira Mavilde , Herdman T. Heather , Gutiérrez Maria G. R.
Published: May 2015

Purpose

To identify and summarize clinical data supporting selection of nursing diagnoses related to the respiratory system for pediatric and neonatal populations.

Method

A literature review conducted in indexed publications was used.

Findings

The final sample consisted of 13 studies conducted in children with cardiac disease, respiratory infection, and asthma with nursing diagnoses such as ineffective breathing pattern, impaired gas exchange, and ineffective airway clearance.

Conclusion

The higher frequency defining characteristics were dyspnea, abnormal breathing pattern, use of accessory muscle to breathe, change in frequency and respiratory rate, decreased SaO2, and agitation.

Implication for Nursing Knowledge

This literature review may provide a basis for consideration of important diagnostic criteria in the pediatric population; however, clinical validation in different stages of development is critical for ensuring diagnostic accuracy.
A pilot study to assess tobacco use among sexual minorities in Houston, Texas
Authors: Tamí‐Maury Irene , Lin Mi‐Ting , Lapham Hillary L. , Hong Judy H. , Cage Catherine , Shete Sanjay , Gritz Ellen R.
Published: May 2015

Background and Objectives

To assess tobacco use among lesbian, gay, bisexual, and transgender (LGBT) individuals from the 2014 Houston Pride Parade and Festival in Houston, Texas (TX).

Methods

Cross‐sectional study using convenience sample of LGBT individuals (n = 99) examining tobacco use, sexual orientation, and other socio‐demographic factors through survey participation.

Results

Findings showed a high prevalence of tobacco and electronic cigarettes use. White LGBT individuals had greater odds of using any type of tobacco product.

Discussion and Conclusions

Despite a high smoking prevalence among the surveyed LGBT individuals, this study sample did not identify tobacco use as a health issue.

Scientific Significance

Supports the need for further investigation on tobacco‐related disparities among LGBT individuals in Houston, TX. (Am J Addict 2015;24:391 –395)
Treatment of male androgenetic alopecia with topical products containing Serenoa repens extract
Authors: Wessagowit Vesarat , Tangjaturonrusamee Chinmanat , Kootiratrakarn Tanawatt , Bunnag Thareena , Pimonrat Tanatya , Muangdang Nattaporn , Pichai Pitchayasak
Published: May 2015

Background/Objectives

Male androgenetic alopecia (AGA) is a common hair problem. Serenoa repens extract has been shown to inhibit both types of 5‐α reductase and, when taken orally, has been shown to increase hair growth in AGA patients. The aim of this study was to assess the efficacy of topical products containing S. repens extract for the treatment of male AGA.

Methods

This was a pilot, prospective, open, within‐subject comparison limited to 24 weeks using no placebo controls. In all, 50 male volunteers aged between 20 and 50 years received topical S. repens products for 24 weeks. The primary end‐point was a hair count in an area of 2.54 cm2 at week 24. Secondary end‐points included hair restoration, investigators' photographic assessment, patients' evaluation and discovering adverse events.

Results

The average hair count and terminal hair count increased at weeks 12 and 24 compared to baseline. Some of these positive results levelled off at week 24, presumably because the concentrated topical product containing S. repens extract was stopped after 4 weeks. The patients were satisfied with the products and the side‐effects were limited.

Conclusions

The topical application of S. repens extract could be an alternative treatment in male pattern baldness in male patients who do not want or cannot tolerate the side‐effects of standard medications, but the use of a concentrated S. repens product beyond 4 weeks may be necessary for sustained efficacy.
Exposure to grass pollen – but not birch pollen – affects lung function in Swedish children
Authors: Gruzieva O. , Pershagen G. , Wickman M. , Melén E. , Hallberg J. , Bellander T. , Lõhmus M.
Published: May 2015

Allergic response to pollen is increasing worldwide, leading to high medical and social costs. However, the effect of pollen exposure on lung function has rarely been investigated. Over 1800 children in the Swedish birth cohort BAMSE were lung‐function‐ and IgE‐tested at the age of 8 and 16 years old. Daily concentrations for 9 pollen types together with measurements for ozone, NO2, PM10, PM2.5 were estimated for the index day as well as up to 6 days before the testing. Exposure to grass pollen during the preceding day was associated with a reduced forced expiratory volume in 8‐yr‐olds; −32.4 ml; 95% CI: −50.6 to −14.2, for an increase in three pollen counts/m³. Associations appeared stronger in children sensitized to pollen allergens. As the grass species flower late in the pollen season, the allergy care routines might be weakened during this period. Therefore, allergy information may need to be updated to increase awareness among grass pollen‐sensitized individuals.
Differential activation of airway eosinophils induces IL‐13‐mediated allergic Th2 pulmonary responses in mice
Authors: Jacobsen E. A. , Doyle A. D. , Colbert D. C. , Zellner K. R. , Protheroe C. A. , LeSuer W. E. , Lee N. A. , Lee J. J.
Published: May 2015

Background

Eosinophils are hallmark cells of allergic Th2 respiratory inflammation. However, the relative importance of eosinophil activation and the induction of effector functions such as the expression of IL‐13 to allergic Th2 pulmonary disease remain to be defined.

Methods

Wild‐type or cytokine‐deficient (IL‐13−/− or IL‐4−/−) eosinophils treated with cytokines (GM‐CSF, IL‐4, IL‐33) were adoptively transferred into eosinophil‐deficient recipient mice subjected to allergen provocation using established models of respiratory inflammation. Allergen‐induced pulmonary changes were assessed.

Results

In contrast to the transfer of untreated blood eosinophils to the lungs of recipient eosinophil deficient mice, which induced no immune/inflammatory changes either in the lung or in the lung draining lymph nodes (LDLN), pretreatment of blood eosinophils with GM‐CSF prior to transfer elicited trafficking of these eosinophils to LDLN. In turn, these LDLN eosinophils elicited the accumulation of dendritic cells and CD4+ T cells to these same LDLNs without inducing pulmonary inflammation. However, exposure of eosinophils to GM‐CSF, IL‐4, and IL‐33 prior to transfer induced not only immune events in the LDLN, but also allergen‐mediated increases in airway Th2 cytokine/chemokine levels, the subsequent accumulation of CD4+ T cells as well as alternatively activated (M2) macrophages, and the induction of pulmonary histopathologies. Significantly, this allergic respiratory inflammation was dependent on eosinophil‐derived IL‐13, whereas IL‐4 expression by eosinophils had no significant role.

Conclusion

The data demonstrate the differential activation of eosinophils as a function of cytokine exposure and suggest that eosinophil‐specific IL‐13 expression by activated cells is a necessary component of the subsequent allergic Th2 pulmonary pathologies.
Genetic approach identifies distinct asthma pathways in overweight vs normal weight children
Authors: Butsch Kovacic M. , Martin L. J. , Biagini Myers J. M. , He H. , Lindsey M. , Mersha T. B. , Khurana Hershey G. K.
Published: May 2015

The pathogenesis of asthma in the context of excess body weight may be distinct from asthma that develops in normal weight children. The study's objective was to explore the biology of asthma in the context of obesity and normal weight status using genetic methodologies. Associations between asthma and SNPs in 49 genes were assessed, as well as, interactions between SNPs and overweight status in child participants of the Greater Cincinnati Pediatric Clinic Repository. Asthma was significantly associated with weight (OR = 1.38; P = 0.037). The number of genes and the magnitude of their associations with asthma were notably greater when considering overweight children alone vs normal weight and overweight children together. When considering weight, distinct sets of asthma‐associated genes were observed, many times with opposing effects. We demonstrated that the underlying heterogeneity of asthma is likely due in part to distinct pathogenetic pathways that depend on preceding/comorbid overweight and/or allergy. It is therefore important to consider both obesity and asthma when conducting studies of asthma.
Estimating leaf area index in tree species using the PocketLAI smart app
Authors: Orlando Francesca , Movedi Ermes , Paleari Livia , Gilardelli Carlo , Foi Marco , Dell'Oro Michele , Confalonieri Roberto
Published: May 2015

Aim

To evaluate the PocketLAI® smart app for estimating leaf area index (LAI) in woody canopies.

Location

Northern Italy.

Methods

PocketLAI – a smartphone application for LAI estimates based on gap fraction derived from the real‐time processing of images acquired at 57° below the canopy – was tested on continuous forest stands, plantations, spotted shrub‐lands and spotted tree‐lands. LAI data from hemispherical photography (images post‐processed with Can‐eye software) were taken as reference values. Plants were clustered on the basis of leaf type and canopy structure.

Results

In general, PocketLAI showed satisfactory performances in the case of broad‐leaf plants (R2 = 0.78, P < 0.001) for all shrub and tree clusters. On the other hand, poor results were obtained for conifers (R2 = 0.16), likely because of the unfavourable leaf area to perimeter ratio. Best performances were observed for dense broad‐leaf canopies characterized by a regular arrangement of crowns (R2 = 0.95 for row‐planted trees, R2 = 0.87 for tall forest trees), although satisfying results were achieved also in the case of canopies made irregular and non‐homogeneous by pruning (R2 = 0.73 for small fruit trees). Concerning shrubs, the agreement between PocketLAI and hemispherical photography was higher for species with big leaves (R2 = 0.72).

Conclusions

These results suggest that PocketLAI can be an alternative to other methods in case of broad‐leaf woody species, especially in contexts where resources and portability are key issues, whereas further improvements are required for conifers.
Moxifloxacin‐induced QTc interval prolongations in healthy male Japanese and Caucasian volunteers: a direct comparison in a thorough QT study
Authors: Morganroth Joel , Wang Yaning , Thorn Michael , Kumagai Yuji , Harris Stuart , Stockbridge Norman , Kleiman Robert , Shah Rashmi
Published: May 2015

Aim

We investigated whether moxifloxacin‐induced QTc prolongations in Japanese and Caucasian healthy male volunteers were significantly different.

Methods

A two period, randomized, crossover, ICH‐E14‐compliant thorough QT (TQT) study compared placebo‐corrected changes in QTc interval from baseline (ΔΔQTcF) and concentration–effect relationships following administration of placebo and 400 mg moxifloxacin to 40 healthy male volunteers from each ethnic population. The point estimates of ΔΔQTcF for each population, and the difference between the two, were calculated at a geometric mean Cmax of moxifloxacin using a linear mixed effects model. The concentration–effect slopes of the two populations were also compared. Equivalence was concluded if the two‐sided 90% confidence interval of the difference in ΔΔQTcF was contained within −5 ms to +5 ms limits and the ratio of the slopes was between 0.5 and 2.

Results

There were no statistically significant differences between the two populations studied, Japanese vs. Caucasians, respectively, for moxifloxacin Cmax (3.27 ± 0.6 vs. 2.98 ± 0.7 µg ml–1), ΔΔQTcF (9.63 ± 1.15 vs. 11.46 ± 1.19 ms at Cmax of 3.07 µg ml–1) and concentration–response slopes (2.58 ± 0.62 vs. 2.34 ± 0.64 ms per µg ml–1). The difference in the two ΔΔQTcF of −1.8 (90% CI −4.6, 0.9) and the ratio of the two slopes (1.1; 90% CI 0.63, 1.82) were within pre‐specified equivalence limits.

Conclusions

Moxifloxacin‐induced QTc prolongations did not differ significantly between the Japanese and Caucasian subjects. However, before our findings are more widely generalized, further studies in other populations and with other QT‐prolonging drugs are needed to clarify whether inter‐ethnic differences in QT sensitivity exist and whether ethnicity of the study population may affect the outcome of a TQT study.
Physiologically‐based pharmacokinetic modeling of renally excreted antiretroviral drugs in pregnant women
Authors: De Sousa Mendes Maïlys , Hirt Deborah , Urien Saik , Valade Elodie , Bouazza Naïm , Foissac Frantz , Blanche Stephane , Treluyer Jean‐Marc , Benaboud Sihem
Published: May 2015

Aim

Physiological changes during pregnancy can affect drug disposition. Anticipating these changes will help to maximize drug efficacy and safety in pregnant women. Our objective was to determine if physiologically‐based pharmacokinetics (PBPK) can accurately predict changes in the disposition of renally excreted antiretroviral drugs during pregnancy.

Methods

Whole body PBPK models were developed for three renally excreted antiretroviral drugs, tenofovir (TFV), emtricitabine (FTC) and lamivudine (3TC). To assess the impact of pregnancy on PK, time‐varying pregnancy‐related physiological parameters available within the p‐PBPK Simcyp® software package were used. Renal clearance during pregnancy followed glomerular filtration changes with or without alterations in secretion. PK profiles were simulated and compared with observed data, i.e. area under the curves (AUC), peak plasma concentrations (Cmax) and oral clearances (CL/F).

Results

PBPK models successfully predicted TFV, FTC and 3TC disposition for non‐pregnant and pregnant populations. Both renal secretion and filtration changed during pregnancy. Changes in renal clearance secretion were related to changes in renal plasma flow. The maximum clearance increases were approximately 30% (TFV 33%, FTC 31%, 3TC 29%).

Conclusions

Pregnancy PBPK models are useful tools to quantify a priori the drug exposure changes during pregnancy for renally excreted drugs. These models can be applied to evaluate alternative dosing regimens to optimize drug therapy during pregnancy.
Cultural universality and specificity of student engagement in school: The results of an international study from 12 countries
Authors: Lam Shui‐fong , Jimerson Shane , Shin Hyeonsook , Cefai Carmel , Veiga Feliciano H. , Hatzichristou Chryse , Polychroni Fotini , Kikas Eve , Wong Bernard P. H. , Stanculescu Elena , Basnett Julie , Duck Robert , Farrell Peter , Liu Yi , Negovan Valeria , Nelson Brett , Yang Hongfei , Zollneritsch Josef
Published: May 2015

Background

A comprehensive understanding of the contextual factors that are linked to student engagement requires research that includes cross‐cultural perspectives.

Aims

This study investigated how student engagement in school is associated with grade, gender, and contextual factors across 12 countries. It also investigated whether these associations vary across countries with different levels of individualism and socio‐economic development.

Samples

The participants were 3,420 7th, 8th, and 9th grade students from Austria, Canada, China, Cyprus, Estonia, Greece, Malta, Portugal, Romania, South Korea, the United Kingdom, and the United States.

Methods

The participants completed a questionnaire to report their engagement in school, the instructional practices they experienced, and the support they received from teachers, peers, and parents. Hierarchical linear modelling was used to examine the effects at both student and country levels.

Results

The results across countries revealed a decline in student engagement from Grade 7 to Grade 9, with girls reporting higher engagement than boys. These trends did not vary across the 12 countries according to the Human Development Index and Hofstede's Individualism Index. Most of the contextual factors (instructional practices, teacher support, and parent support) were positively associated with student engagement. With the exception that parent support had a stronger association with student engagement in countries with higher collectivism, most of the associations between the contextual factors and student engagement did not vary across countries.

Conclusions

The results indicate both cultural universality and specificity regarding contextual factors associated with student engagement in school. They illustrate the advantages of integrating etic and emic approaches in cross‐cultural investigations.
Does mood influence text processing and comprehension? Evidence from an eye‐movement study
Authors: Scrimin Sara , Mason Lucia
Published: May 2015

Background

Previous research has indicated that mood influences cognitive processes. However, there is scarce data regarding the link between everyday emotional states and readers' text processing and comprehension.

Aim

We aim to extend current research on the effects of mood induction on science text processing and comprehension, using eye‐tracking methodology. We investigated whether a positive‐, negative‐, and neutral‐induced mood influences online processing, as revealed by indices of visual behaviour during reading, and offline text comprehension, as revealed by post‐test questions. We were also interested in the link between text processing and comprehension.

Sample

Seventy‐eight undergraduate students randomly assigned to three mood‐induction conditions.

Methods

Students were mood‐induced by watching a video clip. They were then asked to read a scientific text while eye movements were registered. Pre‐ and post‐reading knowledge was assessed through open‐ended questions.

Results

Experimentally induced moods lead readers to process an expository text differently. Overall, students in a positive mood spent significantly longer on the text processing than students in the negative and neutral moods. Eye‐movement patterns indicated more effective processing related to longer proportion of look‐back fixation times in positive‐induced compared with negative‐induced readers. Students in a positive mood also comprehended the text better, learning more factual knowledge, compared with students in the negative group. Only for the positive‐induced readers did the more purposeful second‐pass reading positively predict text comprehension.

Conclusions

New insights are given on the effects of normal mood variations and students' text processing and comprehension by the use of eye‐tracking methodology. Important implications for the role of emotional states in educational settings are highlighted.
Synthesis and Anticholinergic Activity of 4‐hydroxycoumarin Derivatives Containing Substituted Benzyl‐1,2,3‐triazole Moiety
Authors: Bagheri Sahar Mohammad , Khoobi Mehdi , Nadri Hamid , Moradi Alireza , Emami Saeed , Jalili‐Baleh Leili , Jafarpour Farnaz , Homayouni Moghadam Farshad , Foroumadi Alireza , Shafiee Abbas
Published: May 2015

A series of 4‐hydroxycoumarin‐derived compounds 8a‐p containing N‐benzyl‐1,2,3‐triazole motif were designed as AChE inhibitors. The title compounds were obtained conveniently using multicomponent click reaction. The in vitro anticholinesterase evaluation of synthesized compounds against AChE and BuChE showed that some of them are potent and selective inhibitors of AChE. Among them, 2‐chlorobenzyl derivative 8k showed the most potent activity against AChE (IC50 = 0.18 μm). Its activity was also superior to that of standard drug tacrine. The kinetic study and molecular docking simulation of the most potent compound 8k were also described.
A qualitative exploration of the experiences of children with spina bifida and their parents around incontinence and social participation
Authors: Fischer N. , Church P. , Lyons J. , McPherson A. C.
Published: May 2015

Background

Urinary incontinence is frequently experienced by children with spina bifida, putting them at increased risk for low self‐esteem and impacting upon participation in home, school and leisure activities. However, little is known about children's experiences of these continence issues.

Objective

This study explored the experiences of children and young people with spina bifida around continence issues, social participation and peer relationships, in order to identify potential areas of support healthcare professionals can provide.

Methods

Children and youth aged 6–18 years with diagnoses of spina bifida and neurogenic bladder and their parents were invited to participate in semi‐structured interviews. Descriptive thematic analysis was employed.

Results

Eleven children (with a range of mobility levels, types of spina bifida and degrees of bladder control) and their parents participated in the study. Three broad themes were identified, which encompassed the following: (1) normal versus different; (2) independence, ownership and the road to continence; and (3) peer relationships and acceptance.

Discussion

The experiences discussed by the children and parents in this study ranged from minimal impact of incontinence on their day‐to‐day living to significant social isolation and rejection. The stigma of incontinence was apparent in all interviews. Children and youth who were able to control their bladder with minimal accidents had greater independence and more opportunities for social participation. Healthcare professionals need to take into account that parents and their children may differ in attitudes and desires about the management of incontinence.
TRAF3IP3, a novel autophagy up-regulated gene, is involved in marginal zone B lymphocyte development and survival
Authors: Peng S , Wang K , Gu Y , Chen Y , Nan X , Xing J , Cui Q , Chen Y , Ge Q , Zhao H
Published: May 2015

Tumour necrosis factor receptor-associated factor 3 (TRAF3) interacting protein 3 (TRAF3IP3; also known as T3JAM) is expressed specifically in immune organs and tissues. To investigate the impact of TRAF3IP3 on immunity, we generated Traf3ip3 knock-out (KO) mice. Interestingly, these mice exhibited a significant reduction in the number of common lymphoid progenitors (CLPs) and inhibition of B cell development in the bone marrow. Furthermore, Traf3ip3 KO mice lacked marginal zone (MZ) B cells in the spleen. Traf3ip3 KO mice also exhibited a reduced amount of serum natural antibodies and impaired T cell-independent type II (TI–II) responses to trinitrophenol (TNP)-Ficoll antigen. Additionally, our results showed that Traf3ip3 promotes autophagy via an ATG16L1-binding motif, and MZ B cells isolated from mutant mice showed a diminished level of autophagy and a high rate of apoptosis. These results suggest that TRAF3IP3 contributes to MZ B cell survival by up-regulating autophagy, thereby promoting the TI–II immune response.
Expression profiles of RNA‐Seq‐based grey matter‐specific genes versus white matter‐specific genes in grey matter lesions of multiple sclerosis
Authors: Satoh Jun‐ichi , Kino Yoshihiro
Published: May 2015

Objectives

Accumulating evidence shows that formation of cortical grey matter lesions, characterized by accumulation of activated microglia, axonal transection, synaptic loss and neuronal apoptosis, is common in multiple sclerosis (MS) beginning at the early stage. Grey matter lesions are closely associated with disease progression and permanent disability in MS. At present, the precise molecular signature characteristic of grey matter damage in MS brains remains to be intensively characterized.

Methods

To elucidate this, we identified grey matter‐specific genes (GMSG) and white matter‐specific genes (WMSG) abundantly expressed in the normal human brain by analyzing a RNA‐Seq dataset numbered SRP033291, composed of the comprehensive transcriptome of separated grey matter and white matter samples. Then, we studied expression profiles of GMSG and WMSG in MS lesions by analyzing microarray datasets derived from representative cases of grey matter lesions and white matter lesions.

Results

We identified 714 RNA‐Seq‐based GMSG closely related to neuronal functions and 378 WMSG with relevance to glial functions. Numerous WMSG, such as KLK6, GJB1 and MYRF, were downregulated in both grey matter and white matter lesions, whereas the expression of various GMSG, such as PVALB, NEUROD6 and LINGO1, was reduced exclusively in grey matter lesions.

Conclusions

Grey matter lesions of MS are characterized by underexpression of grey matter components, and the panel of RNA‐Seq‐based GMSG and WMSG serves as molecular markers for discrimination between grey matter and white matter lesions of MS.
Orders of Merit and CEO Compensation: Evidence from a Natural Experiment
Authors: Siming Linus
Published: May 2015

Manuscript Type

Empirical

Research Question/Issue

Governments worldwide bestow orders of merit upon their citizens as a recognition of distinguished service. In this paper, I study whether orders of merit can function as an external form of perquisite through which the government can supplement the compensation given by a publicly listed firm to the CEO.

Research Findings/Insights

I build upon the literature on perquisites to develop hypotheses on the relationship between orders of merit and executive compensation. The predictions are tested through an empirical analysis that revolves around the 1974 legal reform in which Sweden discontinued the conferral of orders of merit to citizens. The difference‐in‐differences methodology I employ enables me to make causal statements on the relationship between orders of merit, firm performance, and monetary compensation. I find that orders of merit function as symbols that visibly confirm social status vis‐à‐vis the general public and are valued by CEOs as a substitute for the need to engage in conspicuous consumption.

Theoretical/Academic Implications

This study provides empirical support that orders of merit can be seen as an external form of perquisite that can substitute for monetary compensation. Essentially, this is evidence that governments can affect CEO salaries through the provision of a non‐monetary status good. The findings also indicate that CEOs not only care about distinguishing themselves as “superstars” among their peer group of corporate leaders but also value non‐monetary symbols that emphasize their social status in relation to the general public.

Practitioner/Policy Implications

Companies should take into account that CEOs may receive valuable status goods from the government when determining compensation policies. In addition, governments should consider that the removal of non‐monetary awards may result in higher levels of monetary compensation in publicly listed firms.
The Multidisciplinary Translational Team (MTT) Model for Training and Development of Translational Research Investigators
Authors: Ameredes Bill T. , Hellmich Mark R. , Cestone Christina M. , Wooten Kevin C. , Ottenbacher Kenneth J. , Chonmaitree Tasnee , Anderson Karl E. , Brasier Allan R.
Published: May 2015

Multiinstitutional research collaborations now form the most rapid and productive project execution structures in the health sciences. Effective adoption of a multidisciplinary team research approach is widely accepted as one mechanism enabling rapid translation of new discoveries into interventions in human health. Although the impact of successful team‐based approaches facilitating innovation has been well‐documented, its utility for training a new generation of scientists has not been thoroughly investigated. We describe the characteristics of how multidisciplinary translational teams (MTTs) promote career development of translational research scholars through competency building, interprofessional integration, and team‐based mentoring approaches. Exploratory longitudinal and outcome assessments from our experience show that MTT membership had a positive effect on the development of translational research competencies, as determined by a self‐report survey of 32 scholars. We also observed that all trainees produced a large number of collaborative publications that appeared to be associated with their CTSA association and participation with MTTs. We conclude that the MTT model provides a unique training environment for translational and team‐based learning activities, for investigators at early stages of career development.