bluuebunny/crossref_metadata_2025_split huggingface dataset:
An assay to measure the activity of RNA elements and proteins that promote the expression of mRNA with retained introns
Authors: Jackson Patrick E. H. , Huang Jing , Sharma Monika , Rasmussen Sara K. , Hammarskjold Marie-Louise , Rekosh David 
Published: February 2019

The ability to overcome cellular restrictions that exist for the export and translation of mRNAs with retained introns is a requirement for the replication of retroviruses and also for the expression of many mRNA isoforms transcribed from cellular genes. In some cases, RNA structures have been identified in the mRNA that directly interact with cellular factors to promote the export and expression of isoforms with retained introns. In other cases, a viral protein is also required to act as an adapter. In this report we describe a novel vector system that allows measurement of the ability ofcis-andtrans-acting factors to promote the export and translation of mRNA with retained introns.One reporter vector used in this system is derived from an HIV proviral clone engineered to express two different fluorescent proteins from spliced and unspliced transcripts. The ratio of fluorescent signals is a measurement of the efficiency of export and translation. A second vector utilizes a third fluorescent protein to measure the expression of viral export proteins that interact with some of the export elements. Both vectors can be packaged into viral particles and be used to transduce cells, allowing expression at physiological levels from the integrated vector.
Noradrenergic responsiveness preserves selective attention across the adult life span
Authors: Dahl Martin J. , Mather Mara , Sander Myriam C. , Werkle-Bergner Markus 
Published: February 2019

ABSTRACTSelectively attending to relevant information while blocking out distractors is crucial for goal-directed behavior, yet with advancing age, deficits emerge in attentional selectivity. Decrements in attention have been associated with altered noradrenergic activity in animals. However, research linking noradrenergic functioning to attention in aging humans is scarce, likely reflecting long-standing methodological challenges in non-invasive assessments. We studied whether age-related differences in the noradrenergic system predict differences in attention. We measured pupil dilation, a non-invasive marker of phasic norepinephrine (NE) release, while concurrently recording the electroencephalogram (EEG), of younger (N=39♂; 25.2±3.2 years) and older adults (N=38♂; 70.6±2.7 years). NE release was triggered on a trial-by-trial basis using fear-conditioned (CS+) stimuli. During conditioning, pupil and EEG markers related to heightened NE activity were identified. Afterwards, in a dichotic listening task, participants were cued to direct attention to either the left or right ear while highly similar syllable pairs were presented simultaneously to both ears.During the dichotic listening task, presentation of fear-conditioned stimuli reinstated the acquired fear response, as reflected in pupil and EEG alpha–beta-band responses. Critically, pupil dilation to CS+ was correlated with stronger EEG alpha–beta desynchronization, suggesting a common dependence on NE release. On a behavioral level, NE release facilitated attention. In particular, structural equation modeling revealed that the responsiveness of the NE system is associated with attention on a latent construct level, measured by several indicator tasks. Overall, our results suggest that the responsiveness of the NE system supports attention across the life span.Significance statementIn old age the ability to selectively process relevant aspects of the environment fades. Animal research suggests that the neuromodulator norepinephrine helps to maintain selective attention. We tested younger and older adults across a variety of attention tasks. In addition, we used arousing stimuli to experimentally activate participants’ noradrenergic system while recording pupillometry and electroencephalography (EEG) to infer its functional capacity. Older adults showed compromised attention and reduced noradrenergic responsiveness as indicated by interrelated pupil and EEG markers. Crucially, in both age groups a more responsive noradrenergic system was strongly associated to attention. Our findings link animal and human studies on the neural underpinning of attention in aging and underscore the importance of the noradrenergic system in late life cognition.
High-throughput single-particle tracking reveals nested membrane nanodomain organization that dictates Ras diffusion and trafficking
Authors: Lee Yerim , Phelps Carey , Huang Tao , Mostofian Barmak , Wu Lei , Zhang Ying , Chang Young Hwan , Stork Philip J. S. , Gray Joe W. , Zuckerman Daniel M. , Nan Xiaolin 
Published: February 2019

AbstractMembrane nanodomains have been implicated in Ras signaling, but what these domains are and how they interact with Ras remain obscure. Using high throughput single particle tracking with photoactivated localization microscopy and detailed trajectory analysis, here we show that distinct membrane domains dictate KRas diffusion and trafficking in U2OS cells. KRas exhibits an immobile state in domains ∼70 nm in size, each embedded in a larger domain (∼200 nm) that confers intermediate mobility, while the rest of the membrane supports fast diffusion. Moreover, KRas is continuously removed from the membrane via the immobile state and replenished to the fast state, likely coupled to internalization and recycling. Importantly, both the diffusion and trafficking properties of KRas remain invariant over a broad range of protein expression levels. Our results reveal how membrane organization dictates KRas diffusion and trafficking and offer insight into how Ras signaling may be regulated through spatial mechanisms.
STING polymer structure reveals mechanisms for activation, hyperactivation, and inhibition
Authors: Ergun Sabrina L. , Ferdandez Daniel , Weiss Thomas M. , Li Lingyin 
Published: February 2019

AbstractHow the central innate immune protein, STING, is activated by its ligands remains unknown. Here, using structural biology and biochemistry, we report that the metazoan second messenger 2’3’-cGAMP induces closing of the human STING homodimer and release of the STING C-terminal tail, which exposes a polymerization interface on the STING dimer and leads to the formation of disulfide-linked polymers via cysteine residue 148. Disease-causing hyperactive STING mutations either flank C148 and depend on disulfide formation or reside in the C-terminal tail binding site and cause constitutive C-terminal tail release and polymerization. Finally, bacterial cyclic-di-GMP induces an alternative active STING conformation, activates STING in a cooperative manner, and acts as a partial antagonist of 2’3’-cGAMP signaling. Our insights explain the tight control of STING signaling given varying background activation signals and provide a novel therapeutic hypothesis for autoimmune syndrome treatment.
A transcriptomic atlas of mammalian olfactory mucosae reveals an evolutionary influence on food odor detection in humans
Authors: Saraiva Luis R. , Riveros-McKay Fernando , Mezzavilla Massimo , Abou-Moussa Eman H. , Arayata Charles J. , Trimmer Casey , Ibarra-Soria Ximena , Khan Mona , Gerven Laura Van , Jorissen Mark , Gibbs Matthew , O’Flynn Ciaran , McGrane Scott , Mombaerts Peter , Marioni John C. , Mainland Joel D. , Logan Darren W. 
Published: February 2019

ABSTRACTThe mammalian olfactory system displays species-specific adaptations to different ecological niches. To investigate the evolutionary dynamics of olfactory sensory neuron (OSN) sub-types across 95 million years of mammalian evolution, we applied RNA-sequencing of whole olfactory mucosa samples from mouse, rat, dog, marmoset, macaque and human. We find that OSN subtypes representative of all known mouse chemosensory receptor gene families are present in all analyzed species. Further, we show that OSN subtypes expressing canonical olfactory receptors (ORs) are distributed across a large dynamic range and that homologous subtypes can be either highly abundant across all species or species/order-specific. Interestingly, highly abundant mouse and human OSN subtypes detect odorants with similar sensory profiles, and sense ecologically relevant odorants, such as mouse semiochemicals or human key food odorants. Taken together, our results allow for a better understanding of the evolution of mammalian olfaction in mammals and provide insights into the possible functions of highly abundant OSN subtypes in mouse and human.
Sequencing red fox Y chromosome fragments to develop phylogenetically informative SNP markers and glimpse male-specific trans-Pacific phylogeography
Authors: Sacks BN , Lounsberry ZL , Rando HM , Kluepfel K , Fain S , Brown SK , Kukekova AV 
Published: February 2019

AbstractThe red fox (Vulpes vulpes) has a wide global distribution with many ecotypes, and has been bred in captivity for various traits, making it a useful evolutionary model system. The Y chromosome represents one of the most informative markers of phylogeography, yet it has not been well-studied in the red fox due to a lack of the necessary genomic resources. We used a target capture approach to sequence a portion of the red fox Y chromosome in a geographically diverse red fox sample, along with other canid species, to develop single nucleotide polymorphism (SNP) markers, 13 of which we validated for use in subsequent studies. Phylogenetic analyses of the Y chromosome sequences, including calibration to outgroups, confirmed previous estimates of the timing of two intercontinental exchanges of red foxes, the initial colonization of North America from Eurasia approximately half a million years ago and a subsequent continental exchange before the last Pleistocene glaciation (∼100,000 years ago). However, in contrast to mtDNA, which showed unidirectional transfer from Eurasia to North America prior to the last glaciation, the Y chromosome appears to have been transferred from North America to Eurasia during this period. Additional sampling is needed to confirm this pattern and to further clarify red fox Y chromosome phylogeography.
Highly Efficient Hypothesis Testing Methods for Regression-type Tests with Correlated Observations and Heterogeneous Variance Structure
Authors: Zhang Yun , Bandyopadhyay Gautam , Topham David J. , Falsey Ann R. , Qiu Xing 
Published: February 2019

AbstractBackgroundFor many practical hypothesis testing (H-T) applications, the data are correlated and/or with heterogeneous variance structure. The regressiont-test for weighted linear mixed-effects regression (LMER) is a legitimate choice because it accounts for complex covariance structure; however, high computational costs and occasional convergence issues make it impractical for analyzing high-throughput data. In this paper, we propose computationally efficient parametric and semiparametric tests based on a set of specialized matrix techniques dubbed as the PB-transformation. The PB-transformation has two advantages: 1. The PB-transformed data will have a scalar variance-covariance matrix. 2. The original H-T problem will be reduced to an equivalent one-sample H-T problem. The transformed problem can then be approached by either the one-sample Studentst-test or Wilcoxon signed rank test.ResultsIn simulation studies, the proposed methods outperform commonly used alternative methods under both normal and double exponential distributions. In particular, the PB-transformedt-test produces notably better results than the weighted LMER test, especially in the high correlation case, using only a small fraction of computational cost (3 versus 933 seconds). We apply these two methods to a set of RNA-seq gene expression data collected in a breast cancer study. Pathway analyses show that the PB-transformedt-test reveals more biologically relevant findings in relation to breast cancer than the weighted LMER test․.ConclusionsAs fast and numerically stable replacements for the weighted LMER test, the PB-transformed tests are especially suitable for “messy” high-throughput data that include both independent and matched/repeated samples. By using our method, the practitioners no longer have to choose between using partial data (applying paired tests to only the matched samples) or ignoring the correlation in the data (applying two sample tests to data with some correlated samples).
Molecular chaperones accelerate the evolution of their protein clients in yeast
Authors: Alvarez-Ponce David , Aguilar-Rodríguez José , Fares Mario A. 
Published: February 2019

ABSTRACTProtein stability is a major constraint on protein evolution. Molecular chaperones, also known as heat-shock proteins, can relax this constraint and promote protein evolution by diminishing the deleterious effect of mutations on protein stability and folding. This effect, however, has only been stablished for a few chaperones. Here, we use a comprehensive chaperone-protein interaction network to study the effect of all yeast chaperones on the evolution of their protein substrates, that is, their clients. In particular, we analyze how yeast chaperones affect the evolutionary rates of their clients at two very different evolutionary time scales. We first study the effect of chaperone-mediated folding on protein evolution over the evolutionary divergence ofSaccharomyces cerevisiaeandS. paradoxus. We then test whether yeast chaperones have left a similar signature on the patterns of standing genetic variation found in modern wild and domesticated strains ofS. cerevisiae. We find that genes encoding chaperone clients have diverged faster than genes encoding nonclient proteins when controlling for their number of protein-protein interactions. We also find that genes encoding client proteins have accumulated more intra-specific genetic diversity than those encoding nonclient proteins. In a number of multivariate analyses, controlling by other well-known factors that affect protein evolution, we find that chaperone dependence explains the largest fraction of the observed variance in the rate of evolution at both evolutionary time scales. Chaperones affecting rates of protein evolution mostly belong to two major chaperone families: Hsp70s and Hsp90s. Our analyses show that protein chaperones, by virtue of their ability to buffer destabilizing mutations and their role in modulating protein genotype-phenotype maps, have a considerable accelerating effect on protein evolution.
Anthropogenic Soils Promote Biodiversity in Amazonian Rainforests
Authors: Demetrio Wilian C. , Conrado Ana C. , Acioli Agno , Ferreira Alexandre Casadei , Bartz Marie L.C. , James Samuel W. , Silva Elodie da , Maia Lilianne S. , Martins Gilvan C. , Macedo Rodrigo S. , Stanton David W.G. , Lavelle Patrick , Velasquez Elena , Zangerlé Anne , Barbosa Rafaella , Tapia-Coral Sandra , Muniz Aleksander W. , Santos Alessandra , Ferreira Talita , Segalla Rodrigo F. , Decaëns Thibaud , Nadolny Herlon S. , Peña-Venegas Clara P. , Maia Cláudia S. , Pasini Amarildo , Motta André F. , Taube Júnior Paulo S. , Silva Telma A. , Rebellato Lilian , Júnior Raimundo C. Oliveira , Neves Eduardo , Lima Helena Pinto , Feitosa Rodrigo , Torrado Pablo Vidal , McKey Doyle , Clement Charles R. , Shock Myrtle P. , Teixeira Wenceslau G. , Motta Antônio Carlos V. , de Freitas Melo Vander , Dieckow Jefferson , Garrastazu Marilice , Chubatsu Leda ,   TPI Network, Kille Peter , Brown George G. , Cunha Luís 
Published: February 2019

AbstractAmazonian Dark Earths (ADEs) are fertile anthropic soils found throughout Amazonia, resulting from long-term occupation by pre-Columbian societies. Although the chemistry of these soils is well known, their biodiversity, particularly soil invertebrate communities have been neglected. To address this, we characterised soil macroinvertebrate communities and their activities in ADEs, comparing them with adjacent reference soils under forests and agriculture, at nine archaeological sites. We found 667 morphospecies and a tenacious pre-Columbian biodiversity footprint, with 40% of species found exclusively in ADEs. Soil biological activity was higher in ADEs than in adjacent soils, and associated with higher biomass and richness of organisms known to engineer the ecosystem. We show that these habitats have unique species pools, but that contemporary land-use causes nutrient loss and threatens their diversity. Both past and present human activities alter biodiversity and its distribution in Amazonia, and further efforts are needed to recognize and preserve these ADEs and their biodiversity.
The importance of non‐technical performance for teams managing postpartum haemorrhage: video review of 99 obstetric teams
Authors: Brogaard L , Kierkegaard O , Hvidman L , Jensen KR , Musaeus P , Uldbjerg N , Manser T 
Published: February 2019

ObjectiveLittle is known about how teams’ non‐technical performance influences clinical performance in obstetric emergencies such as postpartum haemorrhage.DesignVideo review – observational study.SettingA university hospital (5000 deliveries) and a regional hospital (2000 deliveries) in Denmark.PopulationObstetric teams managing real‐life postpartum haemorrhage.MethodsWe systematically assessed 99 video recordings of obstetric teams managing real‐life major postpartum haemorrhage. Exposure was the non‐technical score (AOTP); outcomes were the clinical performance score (TeamOBS) and the delayed transfer to the operating theatre (defined as blood loss >1500 ml in the delivery room).ResultsTeams with an excellent non‐technical score performed significantly better than teams with a poor non‐technical score: 83.7 versus 0.3% chance of a high clinical performance score (P < 0.001), 0.2 versus 80% risk of a low clinical performance score (P < 0.001), and 3.5 versus 31.7% risk of delayed transfer to the operating theatre (P = 0.008). The results remained robust when adjusting for potential confounders such as bleeding velocity, aetiology, time of day, team size, and hospital. The specific non‐technical skills associated with high clinical performance were vigilance, role assignment, problem‐solving, management of disruptive behavior, and leadership. Communication with the patient and closing the loop were of minor importance. All performance assessments showed good reliability: the intraclass correlation was 0.97 (95% CI 0.96–0.98) for the non‐technical score and 0.84 (95% CI 0.76–0.89) for the clinical performance score.ConclusionVideo review offers a new method and new perspectives for research in obstetric teams to identify how teams become effective and safe; the skills identified in this study can be included in future obstetric training programmes.Tweetable abstractNon‐technical performance is important for teams managing postpartum haemorrhage; video review of 99 obstetric teams.
Diagnostic reference levels for 18F‐FDG whole body PET/CT procedures: Results from a survey of 12 centres in Australia and New Zealand
Authors: Alkhybari Essam M , McEntee Mark F , Brennan Patrick C , Willowson Kathy P , Kench Peter L 
Published: February 2019

AbstractIntroductionThe aim of this work is to report diagnostic reference levels (DRLs) for hybrid positron emission tomography and x‐ray computed tomography (PET/CT) exams in Australia (AU) for Queensland (QLD) and Western Australia (WA) (AU QLD/WA) and New Zealand (NZ).MethodsTwo‐structured booklets were designed to collect dose information, patient demographics, equipment details and acquisition protocols for fluoride‐18 fluorodeoxyglucose (18F‐FDG) PET/CT procedures, and any additional diagnostic CT routinely performed as part of 18F‐FDG whole‐body examination. The DRL was reported based on the 75th percentile and achievable dose for 18F‐FDG, CT dose index volume (CTDIvol) and dose length product (DLP). The effective dose and total effective dose was reported for 18F‐FDG whole‐body PET/CT examination. Also, the effective dose was reported separately for identified additional diagnostic CT.ResultsThe findings of this study show that the current DRL for 18F‐FDG in AU QLD/WA and NZ was 333.75 MBq and 332.87 MBq, respectively. The reported AU QLD/WA CTDIvol and DLP associated with 18F‐FDG whole‐body PET/CT examinations from vertex to thigh (VT) was 4.41 mGy and 474 mGy.cm. In NZ, the reported VT CTDIvol and DLP was 13.07 mGy and 1319.05 mGy.cm. The effective dose for 18F‐FDG and CT component was 5.6 mSv and 4.7 mSv for AU QLD/WA. For NZ, the effective dose was 5.7 mSv and 10.9 mSv for 18F‐FDG and CT component. The total effective dose delivered from the 18F‐FDG whole‐body scan from the AU QLD/WA PET/CT centres (10.44 mSv) were lower than the radiation doses delivered from the NZ (16.65 mSv).ConclusionsThe current DRLs were proposed for AU QLD/WA and NZ for 18F‐FDG whole‐body PET/CT examinations. Variations existed in the current practice of AU QLD/WA and NZ PET/CT examinations. There is a need to optimize the radiation doses delivered from PET/CT examinations.
Rates and outcomes of total knee replacement for rheumatoid arthritis compared to osteoarthritis
Authors: Mooney Luke , Lewis Peter L. , Campbell David G. , Peng Yi , Hatton Alesha 
Published: February 2019

BackgroundTotal knee replacement (TKR) has been shown to perform differently in patients with rheumatoid arthritis (RA) when compared to osteoarthritis (OA). In this study, we compare the survivorship between these two groups and examine patient and prosthesis factors that impact the revision rate.MethodsAll RA and OA patients undergoing TKR in Australia from 1 September 1999 to 31 December 2016 were included. Revision rates were assessed using Kaplan–Meier estimates of survivorship. The cumulative percent revision analysed age, gender, prosthesis constraint and revision for infection.ResultsThere were 541 744 TKR procedures performed including 7542 patients with RA. RA declined as the primary diagnosis from 2.4% of all TKR in 2003 to 0.9% in 2016. Male sex was an independent revision risk in RA patients (hazard ratio (HR) = 1.66, P < 0.001) and OA patients (3.5 years+: HR = 1.09 (1.04–1.15), P < 0.001). Male RA patients had a higher revision rate for infection than females (HR = 3.14, P < 0.001). Females with RA had a lower cumulative percent revision compared to OA females, but males showed no difference between diagnoses. Revision in RA patients was not influenced by age. Compared to OA, RA patients had a decreased revision rate for those aged <65 years, but not for patients aged ≥65 years.ConclusionThe rate of revision after TKR in RA patients is lower than those with OA, but patients with RA are at increased risk of infection, particularly the male group. Prosthesis constraint had no influence on revision rate. Mortality in those undergoing TKR with RA was higher than in those with OA.