bluuebunny/crossref_metadata_2025 huggingface dataset:
Stereotypical modulations in dynamic functional connectivity explained by changes in BOLD variance
Authors: Glomb Katharina , Ponce-Alvarez Adrián , Gilson Matthieu , Ritter Petra , Deco Gustavo
Published: April 2017

Spontaneous activity measured in human subject under the absence of any task exhibits complex patterns of correlation that largely correspond to large-scale functional topographies obtained with a wide variety of cognitive and perceptual tasks. These “resting state networks” (RSNs) fluctuate over time, forming and dissolving on the scale of seconds to minutes. While these fluctuations, most prominently those of the default mode network, have been linked to cognitive function, it remains unclear whether they result from random noise or whether they index a non-stationary process which could be described as state switching.

In this study, we use a sliding windows-approach to relate temporal dynamics of RSNs to global modulations in correlation and BOLD variance. We compare empirical data, phase-randomized surrogate data, and data simulated with a stationary model. We find that RSN time courses exhibit a large amount of coactivation in all three cases, and that the modulations in their activity are closely linked to global dynamics of the underlying BOLD signal.

We find that many properties of the observed fluctuations in FC and BOLD, including their ranges and their correlations amongst each other, are explained by fluctuations around the average FC structure. However, we also encounter interesting characteristics that are not explained in this way. In particular, we find that the brain spends more time in the troughs of modulations than can be expected from stationary dynamics.
Slow conformational exchange and overall rocking motion in ubiquitin protein crystals
Authors: Kurauskas Vilius , Izmailov Sergei A. , Rogacheva Olga N. , Hessel Audrey , Ayala Isabel , Woodhouse Joyce , Shilova Anastasya , Xue Yi , Yuwen Tairan , Coquelle Nicolas , Colletier Jacques-Philippe , Skrynnikov Nikolai R. , Schanda Paul
Published: April 2017

Proteins perform their functions in solution but their structures are most frequently studied inside crystals. Here we probe how the crystal packing alters microsecond dynamics, using solid-state NMR measurements and multi-microsecond MD simulations of different crystal forms of ubiquitin. In particular, NEar-Rotary-resonance Relaxation Dispersion (NERRD) experiments probe angular backbone motion, while Bloch-McConnell Relaxation Dispersion data report on fluctuations of the local electronic environment. These experiments and simulations reveal that the packing of the protein can significantly alter the thermodynamics and kinetics of local conformational exchange. Moreover, we report small-amplitude reorientational motion of protein molecules in the crystal lattice with a ∼3-5° amplitude on a tens-of-microseconds time scale in one of the crystals, but not in others. An intriguing possibility arises that overall motion is to some extent coupled to local dynamics. Our study highlights the importance of considering the packing when analyzing dynamics of crystalline proteins.
Nanopore Long-Read RNAseq Reveals Widespread Transcriptional Variation Among the Surface Receptors of Individual B cells
Authors: Byrne Ashley , Beaudin Anna E. , Olsen Hugh E. , Jain Miten , Cole Charles , Palmer Theron , DuBois Rebecca M. , Forsberg E. Camilla , Akeson Mark , Vollmers Christopher
Published: April 2017

Understanding gene regulation and function requires a genome-wide method capable of capturing both gene expression levels and isoform diversity at the single cell level. Short-read RNAseq, while the current standard for gene expression quantification, is limited in its ability to resolve complex isoforms because it fails to sequence full-length cDNA copies of RNA molecules. Here, we investigated whether RNAseq using the long-read single-molecule Oxford Nanopore MinION sequencing technology (ONT RNAseq) would be able to identify and quantify complex isoforms without sacrificing accurate gene expression quantification. After successfully benchmarking our experimental and computational approaches on a mixture of synthetic transcripts, we analyzed individual murine B1a cells using a new cellular indexing strategy. Using theMandalorionanalysis pipeline we developed, we identified thousands of unannotated transcription start and end sites, as well as hundreds of alternative splicing events in these B1a cells. We also identified hundreds of genes expressed across B1a cells that displayed multiple complex isoforms, including several B cell specific surface receptors and the antibody heavy chain (IGH) locus. Our results show that not only can we identify complex isoforms, but also quantify their expression, at the single cell level.
Characterizing RNA Pseudouridylation by Convolutional Neural Networks
Authors: He Xuan , Zhang Sai , Zhang Yanqing , Jiang Tao , Zeng Jianyang
Published: April 2017

The most prevalent post-transcriptional RNA modification, pseudouridine (Ψ), also known as the fifth ribonucleoside, is widespread in rRNAs, tRNAs, snRNAs, snoRNAs and mRNAs. Pseudouridines in RNAs are implicated in many aspects of post-transcriptional regulation, such as the maintenance of translation fidelity, control of RNA stability and stabilization of RNA structure. However, our understanding of the functions, mechanisms as well as precise distribution of pseudourdines (especially in mRNAs) still remains largely unclear. Though thousands of RNA pseudouridylation sites have been identified by high-throughput experimental techniques recently, the landscape of pseudouridines across the whole transcriptome has not yet been fully delineated. In this study, we present a highly effective model, called PULSE (PseudoUridyLationSitesEstimator), to predict novel Ψ sites from large-scale profiling data of pseudouridines and characterize the contextual sequence features of pseudouridylation. PULSE employs a deep learning framework, called convolutional neural network (CNN), which has been successfully and widely used for sequence pattern discovery in the literature. Our extensive validation tests demonstrated that PULSE can outperform conventional learning models and achieve high prediction accuracy, thus enabling us to further characterize the transcriptome-wide landscape of pseudouridine sites. Overall, PULSE can provide a useful tool to further investigate the functional roles of pseudouridylation in post-transcriptional regulation.
Modulation of Genome Editing Outcomes by Cell Cycle Control of Cas9 Expression
Authors: Huang Yuping , McCann Caitlin , Samsonov Andrey , Malkov Dmitry , Davis Gregory D , Ji Qingzhou
Published: April 2017

Targeting specific chromosomal sequences for genome modification or regulation during particular phases of the cell cycle may prove useful in creating more precise, predictable genetic changes. Here, we present a system using a fusion protein comprised of a programmable DNA modification protein, Cas9, linked to a cell cycle regulated protein, geminin, as well as green fluorescent protein (GFP) for visualization. Despite the large size of Cas9 relative to geminin, cells were observed to express Cas9-GFP-geminin at levels which oscillate with the cell cycle. These fusion proteins are also shown to retain double-strand break (DSB) activity at specific chromosomal sequences to produce both indels and targeted integration of donor ssDNA. Most importantly, the ratio of ssDNA donor integration to non-homologous end joining (NHEJ) was observed to increase, suggesting that cell cycle control Cas9 expression may be an effective strategy to bias DNA repair outcomes.
Acute transient cognitive dysfunction and acute brain injury induced by systemic inflammation occur by dissociable IL-1-dependent mechanisms
Authors: Skelly Donal T. , Griffin Éadaoin W. , Murray Carol L. , Harney Sarah , O’Boyle Conor , Hennessy Edel , Rawlins J Nicholas , Bannerman David M. , Cunningham Colm
Published: April 2017

Systemic inflammation can impair cognition with relevance to dementia, delirium and post-operative cognitive dysfunction. Acute episodes of delirium also contribute significantly to rates of long-term cognitive decline, implying thatde novopathology occurs during these acute episodes. Whether systemic inflammation-induced acute dysfunction and acute brain injury occur by overlapping or discrete mechanisms has not been investigated. Here we show that systemic inflammation, induced by bacterial LPS, produces both working memory deficits and acute brain injury in the degenerating brain and that these occur by dissociable IL-1-dependent processes. In normal C57BL/6 mice, LPS (100μg/kg) did not affect working memory but robustly impaired contextual fear conditioning (CFC). However prior hippocampal synaptic loss left mice selectively vulnerable to LPS-induced working memory deficits. Systemically administered IL-1 receptor antagonist (IL-1RA) was protective against, and systemic IL-1β replicated, these working memory deficits. Although LPS-induced deficits still occured in IL-1RI-/-mice, systemic TNF-α was sufficient to induce similar deficits, indicating redundancy among these cytokines. Dexamethasone abolished systemic cytokine synthesis and was protective against working memory deficits despite failing to block brain IL-1β synthesis. Direct application of IL-1β to ex vivo hippocampal slices induced non-synaptic depolarisation and irrevesible loss of membrane potential in CA1 neurons from diseased animals and systemic LPS increased apoptosis in the degenerating brain, in an IL-1RI-/-dependent-fashion. The data suggest that LPS induces working memory dysfunction via circulating IL-1β but dysfunction leading to neuronal death is mediated by hippocampal IL-1β. The data suggest that acute systemic inflammation produces both reversible cognitive deficits, resembling delirium, and acute brain injury that may lead to long-term cognitive impairment but that these events are mechanistically dissociable. This would have significant implications for management of cognitive dysfunction and decline during acute illness.
Do gametes woo? Evidence for non-random unions at fertilization
Authors: Nadeau Joseph H.
Published: April 2017

A fundamental tenet of inheritance in sexually reproducing organisms such as humans and laboratory mice is that genetic variants combine randomly at fertilization, thereby ensuring a balanced and statistically predictable representation of inherited variants in each generation. This principle is encapsulated in Mendel’s First Law. But exceptions are known. With transmission ratio distortion (TRD), particular alleles are preferentially transmitted to offspring without reducing reproductive productivity. Preferential transmission usually occurs in one sex but not both and is not known to require interactions between gametes at fertilization. We recently discovered, in our work in mice and in other reports in the literature, instances where any of 12 mutant genes bias fertilization, with either too many or too few heterozygotes and too few homozygotes, depending on the mutant gene and on dietary conditions. Although such deviations are usually attributed to embryonic lethality of the under-represented genotypes, the evidence is more consistent with genetically-determined preferences for specific combinations of egg and sperm at fertilization that results in genotype bias without embryo loss. These genes and diets could bias fertilization in at least three not mutually exclusive ways. They could trigger a reversal in the order of meiotic divisions during oogenesis so that the genetics of fertilizing sperm elicits preferential chromatid segregation, thereby dictating which allele remains in the egg versus the 2ndpolar body. Bias could also result from genetic- and diet-induced anomalies in polyamine metabolism on which function of haploid gametes normally depends. Finally, secreted and cell-surface factors in female reproductive organs could control access of sperm to eggs based on their genetic content. This unexpected discovery of genetically-biased fertilization in mice could yield insights about the molecular and cellular interactions between sperm and egg at fertilization, with implications for our understanding of inheritance, reproduction, population genetics, and medical genetics.
Local processing of visual information in neurites of VGluT3-expressing amacrine cells
Authors: Hsiang Jen-Chun , Johnson Keith , Madisen Linda , Zeng Hongkui , Kerschensteiner Daniel
Published: April 2017

Synaptic inputs to neurons are distributed across extensive neurite arborizations. To what extent arbors process inputs locally or integrate them globally is, for most neurons, unknown. This question is particularly relevant for amacrine cells, a diverse class of retinal interneurons, which receive input and provide output through the same neurites. Here, we used two-photon Ca2+imaging to analyze visual processing in VGluT3-expressing amacrine cells (VG3-ACs), an important component of object motion sensitive circuits in the retina. VG3-AC neurites differed in their preferred stimulus contrast (ON vs. OFF); and ON and OFF responses varied in transience and preferred stimulus size. Contrast preference changed predictably with the laminar position of neurites in the inner plexiform layer. Yet, neurites at all depths were strongly activated by local but not by global image motion. Thus, VG3-AC neurites process visual information locally, exhibiting diverse responses to contrast steps, but uniform object motion selectivity.
Accumulation of RNA on chromatin disrupts heterochromatic silencing
Authors: Brönner Cornelia , Salvi Luca , Zocco Manuel , Ugolini Ilaria , Halic Mario
Published: April 2017

Long noncoding RNAs (lncRNAs) play a conserved role in regulating gene expression, chromatin dynamics, and cell differentiation. They serve as a platform for RNA interference (RNAi)–mediated heterochromatin formation or DNA methylation in many eukaryotic organisms. We found in Schizosaccharomyces pombe that heterochromatin is lost at transcribed regions in the absence of RNA degradation. We show that heterochromatic RNAs are retained on chromatin, form DNA:RNA hybrids, and need to be degraded by the Ccr4-Not complex or RNAi to maintain heterochromatic silencing. The Ccr4-Not complex is localized to chromatin independently of H3K9me and degrades chromatin-associated transcripts, which is required for transcriptional silencing. Overexpression of heterochromatic RNA, but not euchromatic RNA, leads to chromatin localization and loss of silencing of a distant ade6 reporter in wild-type cells. Our results demonstrate that chromatin-bound RNAs disrupt heterochromatin organization and need to be degraded in a process of heterochromatin formation.
Acyl-CoA:Lysophosphatidylethanolamine Acyltransferase Activity Regulates Growth of Arabidopsis
Authors: Jasieniecka-Gazarkiewicz Katarzyna , Lager Ida , Carlsson Anders S. , Gutbrod Katharina , Peisker Helga , Dörmann Peter , Stymne Sten , Banaś Antoni
Published: April 2017

Arabidopsis (Arabidopsis thaliana) contains two enzymes (encoded by the At1g80950 and At2g45670 genes) preferentially acylating lysophosphatidylethanolamine (LPE) with acyl-coenzyme A (CoA), designated LYSOPHOSPHATIDYLETHANOLAMINE ACYLTRANSFERASE1 (LPEAT1) and LPEAT2. The transfer DNA insertion mutant lpeat2 and the double mutant lpeat1 lpeat2 showed impaired growth, smaller leaves, shorter roots, less seed setting, and reduced lipid content per fresh weight in roots and seeds and large increases in LPE and lysophosphatidylcholine (LPC) contents in leaves. Microsomal preparations from leaves of these mutants showed around 70% decrease in acylation activity of LPE with 16:0-CoA compared with wild-type membranes, whereas the acylation with 18:1-CoA was much less affected, demonstrating that other lysophospholipid acyltransferases than the two LPEATs could acylate LPE. The above-mentioned effects were less pronounced in the single lpeat1 mutant. Overexpression of either LPEAT1 or LPEAT2 under the control of the 35S promotor led to morphological changes opposite to what was seen in the transfer DNA mutants. Acyl specificity studies showed that LPEAT1 utilized 16:0-CoA at the highest rate of 11 tested acyl-CoAs, whereas LPEAT2 utilized 20:0-CoA as the best acyl donor. Both LPEATs could acylate either sn position of ether analogs of LPC. The data show that the activities of LPEAT1 and LPEAT2 are, in a complementary way, involved in growth regulation in Arabidopsis. It is shown that LPEAT activity (especially LPEAT2) is essential for maintaining adequate levels of phosphatidylethanolamine, LPE, and LPC in the cells.
Modelling and validation of particle size distributions of supported nanoparticles using the pair distribution function technique
Authors: Gamez-Mendoza Liliana , Terban Maxwell W. , Billinge Simon J. L. , Martinez-Inesta Maria
Published: April 2017

The particle size of supported catalysts is a key characteristic for determining structure–property relationships. It is a challenge to obtain this information accurately and in situ using crystallographic methods owing to the small size of such particles (<5 nm) and the fact that they are supported. In this work, the pair distribution function (PDF) technique was used to obtain the particle size distribution of supported Pt catalysts as they grow under typical synthesis conditions. The PDF of Pt nanoparticles grown on zeolite X was isolated and refined using two models: a monodisperse spherical model (single particle size) and a lognormal size distribution. The results were compared and validated using scanning transmission electron microscopy (STEM) results. Both models describe the same trends in average particle size with temperature, but the results of the number-weighted lognormal size distributions can also accurately describe the mean size and the width of the size distributions obtained from STEM. Since the PDF yields crystallite sizes, these results suggest that the grown Pt nanoparticles are monocrystalline. This work shows that refinement of the PDF of small supported monocrystalline nanoparticles can yield accurate mean particle sizes and distributions.
The mediating role of ambidextrous capability in learning orientation and new product performance
Authors: Huang Jing-Wen , Li Yong-Hui
Published: April 2017

Purpose

Learning orientation is critical in new product development. However, research has disregarded how learning orientation operates via the potential mediator to influence new product performance. The purpose of this study is to examine the mediating role of ambidextrous capability in the relationship between learning orientation and new product performance.

Design/methodology/approach

The empirical study uses a questionnaire approach designed to collect data for testing research hypotheses. This study tests the hypotheses using structural equation model in a sample of 336 firms in Taiwan.

Findings

The findings indicate that learning orientation relates positively to ambidextrous capability and new product performance. Ambidextrous capability, in turn, relates positively to new product performance. The results also support the argument that ambidextrous capability plays a mediating role in learning orientation and new product performance.

Originality/value

The value of this study is to identify ambidextrous capability as the potential mediator in the relationship between learning orientation and new product performance. The results enrich the understanding of learning orientation in new product project teams and suggest important implications for new product development and future research.
Tax compliance of small and medium enterprises: a developing country perspective
Authors: Musimenta Doreen , Nkundabanyanga Stephen Korutaro , Muhwezi Moses , Akankunda Brenda , Nalukenge Irene
Published: April 2017

Purpose

The purpose of this paper is to establish the relationship between tax fairness, isomorphic forces, strategic responses and tax compliance in Ugandan small and medium enterprises (SMEs).

Design/methodology/approach

This is a correlational and cross-sectional study using two respondent types, the demand (represented by the tax collecting body respondents) and supply (represented by SME respondents) sides of tax compliance, to examine perceived tax compliance in Uganda’s SMEs.

Findings

Tax fairness, isomorphic forces and strategic responses have a predictive force on tax compliance. Significant mediation effects of tax fairness and also strategic responses are found. The two respondent types perceive the study variables differently – providing an understanding of why the tax compliance puzzle has remained a burgeoning concern. For example, the tax-collecting body respondents perceived more tax fairness than SME respondents, suggesting that perceived tax fairness depends on whose “lenses” you look through.

Research limitations/implications

Rather than focussing only on the importance of the rational analytical deliberation of tax fairness by taxpayers in influencing their tax compliance, the current paper shows that in addition, isomorphic forces and strategic responses establish the basis for understanding taxpayers’ compliance.

Originality/value

The methodology that enlists two respondent types, i.e. the supply side of tax compliance and the demand side of tax compliance, probably offers a unique way of deriving better results than previous studies.
Reforms and identities
Authors: Glinka Beata , Hensel Przemyslaw G.
Published: April 2017

Purpose

The purpose of this paper is to show how the identities of the employees of Polish public administration are shaped in the process of public system reforms.

Design/methodology/approach

The findings are based on interviews with 40 employees of the Polish public administration. The authors have used open interviews as well as projective methods to discover and explore beliefs and attitudes of bureaucrats towards their work and the system of public administration. The selected sample was diversified both spatially and systematically to reflect the diversity of organisations that constitute the Polish public administration system. Grounded theory was used for data coding and interpretation.

Findings

The study indicates that organisational change initiatives designed to enhance the quality and efficiency of public administration may have negative impacts on the identities of public servants and may lead to their increased incapacity. Rather than sparking entrepreneurial behaviours and transforming bureaucrats into managers, introduction of the rhetoric of New Public Management and New Public Governance in the Polish public administration has contributed to strengthening of classical dysfunctions of bureaucracy.

Research limitations/implications

The results imply that the understanding of organisational changes in the Eastern European public sector – which are usually studied through the lenses of regulation and economy – would benefit from more sociologically and historically oriented studies. The limitations of our results are associated with the adopted qualitative subjective methodology.

Practical implications

Foreign-born templates of reforms may appear to be logical and coherent but they rest on certain assumptions about identities and value structures that are not necessarily congruent with the identities at the adoption site. For that reason, successful reform projects need to consider and problematise the content and shape of culturally conditioned identities.

Social implications

Understanding of public sector reforms’ implication should lead to the improvement of change programmes as well as to the evolution of public administration towards a form more desired by the society. It is especially important as Polish society considers public administration as one of factors influencing (in a negative way) the quality of life.

Originality/value

The paper provides insight into public administration reforms in Poland and their impact on public servants’ identities.
The mobility of mitochondria: Intercellular trafficking in health and disease
Authors: Berridge Michael V , Neuzil Jiri
Published: April 2017

The view that genes are constrained within somatic cells is challenged by in vitro evidence, and more recently by in vivo studies which demonstrate that mitochondria with their mitochondrial DNA (mtDNA) payload not only can, but do move between cells in tumour models and in mouse models of tissue damage. Using mouse tumour cell models without mtDNA to reflect mtDNA damage, we have shown that these cells grow tumours only after acquiring mtDNA from cells in the local microenvironment resulting in respiration recovery, tumorigenesis and metastasis. Mitochondrial transfer between cells has also been demonstrated following ischaemia‐induced injury in the heart and brain and in lung epithelium, and following lung inflammation. In vitro investigations suggest that stem cells may be mitochondrial donors. The ability of mitochondria to move between cells appears to be an evolutionarily‐conserved phenomenon, relevant to diseases with compromised mitochondrial function including neurodegenerative, neuromuscular and cardiovascular diseases as well as cancer and ageing.
Strategies of Resistance: Diversification and Diffusion
Authors: Cunningham Kathleen Gallagher , Dahl Marianne , Frugé Anne
Published: April 2017

Why do organizations choose to use nonviolence? Why do they choose specific nonviolent tactics? Existing quantitative work centers on mass nonviolent campaign, but much of the nonviolence employed in contentious politics is smaller‐scale nonviolent direct action. In this article, we explore the determinants of nonviolence with new data at the organization level in self‐determination disputes from 1960 to 2005. We present a novel argument about the interdependence of tactical choices among nonviolent options in self‐determination movements. Given limitations on their capabilities, competition among organizations in a shared movement, and different resource requirements for nonviolent strategies, we show that organizations have incentives to diversify tactics rather than just copy other organizations. The empirical analysis reveals a rich picture of varied organizational resistance choices, and a complex web of interdependence among tactics.
Association of glucagon‐like peptide‐1 receptor agonist use and rates of acute myocardial infarction, stroke and overall mortality in patients with type 2 diabetes mellitus in a large integrated health system
Authors: Zimmerman Robert S. , Hobbs Todd M. , Wells Brian J. , Kong Sheldon X. , Kattan Michael W. , Bouchard Jon , Chagin Kevin M. , Yu Changhong , Sakurada Brian , Milinovich Alex , Weng Wayne , Bauman Janine M. , Pantalone Kevin M.
Published: April 2017

Aims

To assess the potential impact of glucagon‐like peptide‐1 receptor agonist (GLP‐1RA) exposure on cardiovascular disease (CVD) and mortality outcomes in patients with type 2 diabetes (T2D), using a large retrospective cohort.

Research Design and Methods

Patients who had T2D between 2005 and 2014 (N = 105 862) were identified from the electronic health record system at Cleveland Clinic using a validated electronic phenotype. A time‐dependent, Cox, multiple regression analysis was used to assess the association between GLP‐1RA exposure and risk of acute myocardial infarction (AMI), stroke/cerebrovascular accident (CVA), and overall mortality, as well as the composite of all three outcomes. The findings were further evaluated by assessing the effect of GLP‐1RAs on the same variables in patients with and without prior CVD. The model adjusted for differences in demographic information, hypertension, laboratory/vital signs, history of outcomes, and T2D medications.

Results

There were significantly lower rates of AMI (hazard ratio [HR] 0.80, 95% confidence interval [CI] 0.65 to 0.99; P = .045), CVA (HR 0.82, 95% CI 0.74 to 0.91, P < .001), overall mortality (HR 0.48, 95% CI 0.41 to 0.57; P < .001), and the composite outcome (HR 0.82, 95% CI 0.74 to 0.91; P < .002) during the consolidated time that patients were exposed to GLP‐1RAs compared to corresponding rates during intervals without GLP‐1RA exposure. GLP‐1RA treatment was associated with a significant decrease in CVA, mortality, and the composite outcome in patients with and without established CVD, not significantly affecting AMI in these subgroups.

Conclusions

GLP‐1RA exposure was found to be associated with a reduction in the risk of cardiovascular events observed and overall mortality among patients with T2D with and without established CVD, after adjusting for potential confounders.
ACCOUNTING FOR COMPLEMENTARY SKILL SETS: EVALUATING INDIVIDUAL MARGINAL VALUE TO A TEAM IN THE NATIONAL BASKETBALL ASSOCIATION
Authors: Kuehn Joseph
Published: April 2017

Identifying an individual worker's contribution to firm production can be difficult in a team setting where spillovers in labor productivity exist among team members. This paper studies a model of labor productivity where workers have heterogeneous abilities, and can differently affect the productivity of their fellow teammates. Applying the model to the setting of the National Basketball Association (NBA), I can identify the marginal value that a basketball player brings to a particular team lineup, both through his own individual contributions and his complementary contribution to teammates' productivity. Estimates from the model imply that teammates have a significant impact on individual player productivity, and that taking into account spillovers across teammates is important to assessing both overall team productivity and an individual player's contribution to team productivity. I then evaluate whether player complementarities are valued in the NBA labor market in terms of higher salaries, and find that they are undervalued, and that players are instead paid mainly for their individual offensive production. This creates an asymmetry between player incentives and the team objective. To assess the size of this inefficiency, the top trading cycle algorithm of Shapley and Scarf (1974) is used to identify a Pareto optimal matching between players and teams, that accounts for the complementarities between heterogeneous players' skill sets. (JEL J30, L25, L83, M51)
Acetylcholine modulates gamma frequency oscillations in the hippocampus by activation of muscarinic M1 receptors
Authors: Betterton Ruth T. , Broad Lisa M. , Tsaneva‐Atanasova Krasimira , Mellor Jack R.
Published: April 2017

Modulation of gamma oscillations is important for the processing of information and the disruption of gamma oscillations is a prominent feature of schizophrenia and Alzheimer's disease. Gamma oscillations are generated by the interaction of excitatory and inhibitory neurons where their precise frequency and amplitude are controlled by the balance of excitation and inhibition. Acetylcholine enhances the intrinsic excitability of pyramidal neurons and suppresses both excitatory and inhibitory synaptic transmission, but the net modulatory effect on gamma oscillations is not known. Here, we find that the power, but not frequency, of optogenetically induced gamma oscillations in the CA3 region of mouse hippocampal slices is enhanced by low concentrations of the broad‐spectrum cholinergic agonist carbachol but reduced at higher concentrations. This bidirectional modulation of gamma oscillations is replicated within a mathematical model by neuronal depolarisation, but not by reducing synaptic conductances, mimicking the effects of muscarinic M1 receptor activation. The predicted role for M1 receptors was supported experimentally; bidirectional modulation of gamma oscillations by acetylcholine was replicated by a selective M1 receptor agonist and prevented by genetic deletion of M1 receptors. These results reveal that acetylcholine release in CA3 of the hippocampus modulates gamma oscillation power but not frequency in a bidirectional and dose‐dependent manner by acting primarily through muscarinic M1 receptors.
Phenobarbital in intensive care unit pediatric population: predictive performances of population pharmacokinetic model
Authors: Marsot Amélie , Michel Fabrice , Chasseloup Estelle , Paut Olivier , Guilhaumou Romain , Blin Olivier
Published: April 2017

An external evaluation of phenobarbital population pharmacokinetic model described by Marsot et al. was performed in pediatric intensive care unit. Model evaluation is an important issue for dose adjustment. This external evaluation should allow confirming the proposed dosage adaptation and extending these recommendations to the entire intensive care pediatric population. External evaluation of phenobarbital published population pharmacokinetic model of Marsot et al. was realized in a new retrospective dataset of 35 patients hospitalized in a pediatric intensive care unit. The published population pharmacokinetic model was implemented in nonmem 7.3. Predictive performance was assessed by quantifying bias and inaccuracy of model prediction. Normalized prediction distribution errors (NPDE) and visual predictive check (VPC) were also evaluated. A total of 35 infants were studied with a mean age of 33.5 weeks (range: 12 days–16 years) and a mean weight of 12.6 kg (range: 2.7–70.0 kg). The model predicted the observed phenobarbital concentrations with a reasonable bias and inaccuracy. The median prediction error was 3.03% (95% CI: −8.52 to 58.12%), and the median absolute prediction error was 26.20% (95% CI: 13.07–75.59%). No trends in NPDE and VPC were observed. The model previously proposed by Marsot et al. in neonates hospitalized in intensive care unit was externally validated for IV infusion administration. The model‐based dosing regimen was extended in all pediatric intensive care unit to optimize treatment. Due to inter‐ and intravariability in pharmacokinetic model, this dosing regimen should be combined with therapeutic drug monitoring.
Rifampicin reverses nicardipine effect inducing uncontrolled essential hypertension
Authors: Cordeanu Elena‐Mihaela , Gaertner Sébastien , Faller Alix , Mirea Corina , Lessinger Jean‐Marc , Kemmel Veronique , Stephan Dominique
Published: April 2017

Dihydropyridine calcium‐channel blockers are a known substrate for the cytochrome P450 isoform 3A4. Rifampicin, an antitubercular agent, is one of the most potent inducers of hepatic and intestinal CYP3A4 thus increasing dihydropyridine metabolism. We report a case of a 67‐year‐old hypertensive female treated with a four‐drug antihypertensive regimen including a dihydropyridine (nicardipine 50 mg bid), who was admitted for septic arthritis of the knee requiring antibiotic treatment with teicoplanin 400 mg od and rifampicin 600 mg bid. Six days after rifampicin initiation, she presented with Posterior Reversible Encephalopathy Syndrome due to uncontrolled hypertension. We hypothesized that disequilibrium of previously controlled hypertension was partially due to nicardipine ineffectiveness. Plasma nicardipine concentration was assessed through high‐performance liquid chromatography 5 hours after coadministration of the two drugs and proved undetectable.
Reduced Healthcare Use and Apparent Savings with Passive Home Monitoring Technology: A Pilot Study
Authors: Finch Michael , Griffin Kristen , Pacala James T.
Published: April 2017

Objectives

To conduct a cost analysis of ambient assisted living technology, which is promising for improving the ability of individuals and care providers to monitor daily activities and gain better awareness through proactive management of health and safety.

Design

Three‐arm cohort study.

Setting

Homes of enrollees of a state‐based healthcare plan for older adults.

Participants

Enrollees dually eligible for Medicare and Medicaid (N = 268).

Intervention

Health and safety passive remote patient monitoring (PRPM) systems were installed in enrollees’ homes (the intervention group) with monitoring and proactive intervention of a case manager when deviation from baseline subject behavior was detected.

Measurements

Claims data were collected over 12 months to assess healthcare use and costs in the intervention group and to compare use and costs with those of two control groups: a concurrent group of enrollees who declined the technology and a historical cohort matched on age to the participation group.

Results

Although the small sample size precluded cost differences that were statistically significant, the participant group used substantially less custodial care, emergency department (ED) services, inpatient stays, and ED costs than the two control groups.

Conclusion

In this pilot study, the PRPM system was associated with apparent healthcare cost savings. Although more cost analyses are warranted, ambient assisted living technologies are a potentially valuable investment for older adult care.
Simulations of membrane‐bound diglycosylated human prion protein reveal potential protective mechanisms against misfolding
Authors: Cheng Chin Jung , Koldsø Heidi , Van der Kamp Marc W. , Schiøtt Birgit , Daggett Valerie
Published: April 2017

Prion diseases are associated with the misfolding of the prion protein (PrP) from its normal cellular form (PrPC) to its infectious scrapie form (PrPSc). Post‐translational modifications in PrP in vivo can play an important role in modulating the process of misfolding. To gain more insight into the effects of post‐translational modifications in PrP structure and dynamics and to test the hypothesis that such modifications can interact with the protein, we have performed molecular dynamics simulations of diglycosylated human PrPC bound to a lipid bilayer via a glycophosphatidylinositol anchor. Multiple simulations were performed at three different pH ranges to explore pH effects on structure and dynamics. In contrast to simulations of protein‐only PrPC, no large effects were observed upon lowering the pH of the system. The protein tilted toward the membrane surface in all of the simulations and the putative PrPSc oligomerization sites became inaccessible, thereby offering a possible protective mechanism against PrPSc‐induced misfolding of PrPC.

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Biomarkers of microvascular endothelial dysfunction predict incident dementia: a population‐based prospective study
Authors: Holm H. , Nägga K. , Nilsson E. D. , Ricci F. , Melander O. , Hansson O. , Bachus E. , Magnusson M. , Fedorowski A.
Published: April 2017

Background

Cerebral endothelial dysfunction occurs in a spectrum of neurodegenerative diseases. Whether biomarkers of microvascular endothelial dysfunction can predict dementia is largely unknown. We explored the longitudinal association of midregional pro‐atrial natriuretic peptide (MR‐proANP), C‐terminal endothelin‐1 (CT‐proET‐1) and midregional proadrenomedullin (MR‐proADM) with dementia and subtypes amongst community‐dwelling older adults.

Methods

A population‐based cohort of 5347 individuals (men, 70%; age, 69 ± 6 years) without prevalent dementia provided plasma for determination of MR‐proANP, CT‐proET‐1 and MR‐proADM. Three‐hundred‐and‐seventy‐three patients (7%) were diagnosed with dementia (120 Alzheimer's disease, 83 vascular, 102 mixed, and 68 other aetiology) over a period of 4.6 ± 1.3 years. Relations between baseline biomarker plasma concentrations and incident dementia were assessed using multivariable Cox regression analysis.

Results

Higher levels of MR‐proANP were significantly associated with increased risk of all‐cause and vascular dementia (hazard ratio [HR] per 1 SD: 1.20, 95% confidence interval [CI], 1.07–1.36; P = 0.002, and 1.52; 1.21–1.89; P < 0.001, respectively). Risk of all‐cause dementia increased across the quartiles of MR‐proANP (p for linear trend = 0.004; Q4, 145–1681 pmol L−1 vs. Q1, 22–77 pmol L−1: HR: 1.83; 95%CI: 1.23–2.71) and was most pronounced for vascular type (p for linear trend = 0.005: HR: 2.71; 95%CI: 1.14–6.46). Moreover, the two highest quartiles of CT‐proET‐1 predicted vascular dementia with a cut‐off value at 68 pmol L−1 (Q3–Q4, 68–432 pmol L−1 vs. Q1–Q2,4–68 pmol L−1; HR: 1.94; 95%CI: 1.12–3.36). Elevated levels of MR‐proADM indicated no increased risk of developing dementia after adjustment for traditional risk factors.

Conclusions

Elevated plasma concentration of MR‐proANP is an independent predictor of all‐cause and vascular dementia. Pronounced increase in CT‐proET‐1 indicates higher risk of vascular dementia.
Methods of RNA preparation affect mRNA abundance quantification of reference genes in pig maturing oocytes
Authors: Wang Y‐K , Li X , Song Z‐Q , Yang C‐X
Published: April 2017

Contents

To ensure accurate normalization and quantification of target RNA transcripts using reverse transcription quantitative polymerase chain reaction (RT‐qPCR), most studies focus on the identification of stably expressed gene(s) as internal reference. However, RNA preparation methods could also be an important factor, especially for test samples of limited quantity (e.g. oocytes). In this study, we aimed to select appropriate reference gene(s), and evaluate the effect of RNA preparation methods on gene expression quantification in porcine oocytes and cumulus cells during in vitro maturation. Expression profiles of seven genes (GAPDH, 18S, YWHAG, BACT, RPL4, HPRT1 and PPIA) were examined, on RNA samples extracted from cumulus cells (RNeasy Kit) and oocytes (RNeasy Kit and Lysis Kit) during in vitro maturation, respectively. Interestingly, different RNA preparation methods were found to potentially affect the quantification of reference gene expression in pig oocytes cultured in vitro. After geNorm analyses, the most suitable genes for normalization were identified, GAPDH/18S for cumulus cells and YWHAG/BACT for oocytes, respectively. Thus, our results provide useful data and information on the selection of better reference genes and RNA preparation method for related functional studies.
Response to a combination of oxygen and a hypnotic as treatment for obstructive sleep apnoea is predicted by a patient's therapeutic CPAP requirement
Authors: Landry Shane A. , Joosten Simon A. , Sands Scott A. , White David P. , Malhotra Atul , Wellman Andrew , Hamilton Garun S. , Edwards Bradley A.
Published: April 2017

ABSTRACT

Background and objective

Upper airway collapsibility predicts the response to several non‐continuous positive airway pressure (CPAP) interventions for obstructive sleep apnoea (OSA). Measures of upper airway collapsibility cannot be easily performed in a clinical context; however, a patient's therapeutic CPAP requirement may serve as a surrogate measure of collapsibility. The present work aimed to compare the predictive use of CPAP level with detailed physiological measures of collapsibility.

Methods

Therapeutic CPAP levels and gold‐standard pharyngeal collapsibility measures (passive pharyngeal critical closing pressure (Pcrit) and ventilation at CPAP level of 0 cmH2O (Vpassive)) were retrospectively analysed from a randomized controlled trial (n = 20) comparing the combination of oxygen and eszopiclone (treatment) versus placebo/air control. Responders (9/20) to treatment were defined as those who exhibited a 50% reduction in apnoea/hypopnoea index (AHI) plus an AHI<15 events/h on‐therapy.

Results

Responders to treatment had a lower therapeutic CPAP requirement compared with non‐responders (6.6 (5.4–8.1)  cmH2O vs 8.9 (8.4–10.4) cmH2O, P = 0.007), consistent with their reduced collapsibility (lower Pcrit, P = 0.017, higher Vpassive P = 0.025). Therapeutic CPAP level provided the highest predictive accuracy for differentiating responders from non‐responders (area under the curve (AUC) = 0.86 ± 0.9, 95% CI: 0.68–1.00, P = 0.007). However, both Pcrit (AUC = 0.83 ± 0.11, 95% CI: 0.62–1.00, P = 0.017) and Vpassive (AUC = 0.77 ± 0.12, 95% CI: 0.53–1.00, P = 0.44) performed well, and the difference in AUC for these three metrics was not statistically different. A therapeutic CPAP level ≤8 cmH2O provided 78% sensitivity and 82% specificity (positive predictive value = 78%, negative predictive value = 82%) for predicting a response to these therapies.

Conclusion

Therapeutic CPAP requirement, as a surrogate measure of pharyngeal collapsibility, predicts the response to non‐anatomical therapy (oxygen and eszopiclone) for OSA.
Optimal Social Security with Imperfect Tagging
Authors: Denk Oliver , Michau Jean‐Baptiste
Published: April 2017

Workers are exposed to the risk of permanent disability. We rely on a dynamic mechanism design approach to determine how imperfect information on health should optimally be used to improve the trade‐off between inducing the able to work and providing insurance against disability. The government should offer back‐loaded incentives and exploit the information revealed by the gap between the age at which disability occurs and the age of eligibility to disability benefits. Furthermore, the able who are (mistakenly) tagged as disabled should be encouraged to work until some early retirement age.
Abnormal Rab11‐Rab8‐vesicles cluster in enterocytes of patients with microvillus inclusion disease
Authors: Vogel Georg F. , Janecke Andreas R. , Krainer Iris M. , Gutleben Karin , Witting Barbara , Mitton Sally G. , Mansour Sahar , Ballauff Antje , Roland Joseph T. , Engevik Amy C. , Cutz Ernest , Müller Thomas , Goldenring James R. , Huber Lukas A. , Hess Michael W.
Published: April 2017

Microvillus inclusion disease (MVID) is a congenital enteropathy characterized by accumulation of vesiculo‐tubular endomembranes in the subapical cytoplasm of enterocytes, historically termed “secretory granules.” However, neither their identity nor pathophysiological significance is well defined. Using immunoelectron microscopy and tomography, we studied biopsies from MVID patients (3× Myosin 5b mutations and 1× Syntaxin3 mutation) and compared them to controls and genome‐edited CaCo2 cell models, harboring relevant mutations. Duodenal biopsies from 2 patients with novel Myosin 5b mutations and typical clinical symptoms showed unusual ultrastructural phenotypes: aberrant subapical vesicles and tubules were prominent in the enterocytes, though other histological hallmarks of MVID were almost absent (ectopic intra‐/intercellular microvilli, brush border atrophy). We identified these enigmatic vesiculo‐tubular organelles as Rab11‐Rab8‐positive recycling compartments of altered size, shape and location harboring the apical SNARE Syntaxin3, apical transporters sodium‐hydrogen exchanger 3 (NHE3) and cystic fibrosis transmembrane conductance regulator. Our data strongly indicate that in MVID disrupted trafficking between cargo vesicles and the apical plasma membrane is the primary cause of a defect of epithelial polarity and subsequent facultative loss of brush border integrity, leading to malabsorption. Furthermore, they support the notion that mislocalization of transporters, such as NHE3 substantially contributes to the reported sodium loss diarrhea.
Current conduction mechanisms through thin tunnel oxide during erase operation of flash electrically erasable programmable read-only memory devices
Authors: Samanta Piyas
Published: April 2017

The mechanism of current conduction through thin tunnel oxide during erase operation of flash electrically erasable programmable read-only memory devices has been studied both theoretically and experimentally. The floating gate (FG) leakage current measured between 25 and 300 °C and at oxide fields ranging from 6 to 10 MV/cm is primarily attributed to Poole–Frenkel (PF) emission of trapped electrons from the electron traps located at about 1.0 eV below the silicon dioxide conduction band in addition to Fowler–Nordheim (FN) tunneling of electrons from the degenerately doped n-type polycrystalline silicon (n+-polySi) FG. It is observed that PF emission current IPF dominates FN electron tunneling current IFN at oxide electric fields Eox between 6 and 10 MV/cm and throughout the temperature range studied here. The observed thickness dependence of FG leakage current at a given applied oxide field arises due to different electron trap concentrations in the oxide. A physics based new temperature dependent analytical formula has also been developed for FN tunneling of electrons from the accumulation layer of semiconductors. In addition, the authors present theoretical results showing the effect of the FG doping concentration on the leakage current.