bluuebunny/crossref_metadata_2025 huggingface dataset:
Sleep indices and eating behaviours in young adults: findings from Project EAT
Authors: Ogilvie Rachel P , Lutsey Pamela L , Widome Rachel , Laska Melissa N , Larson Nicole , Neumark-Sztainer Dianne
Published: December 2017

Objective

To test the associations between sleep indices and eating behaviours in young adults, a group vulnerable to suboptimal sleep.

Design

Cross-sectional analysis of survey measures of sleep (i.e. time in bed, variability, timing and quality) and dietary patterns (i.e. breakfast skipping, eating at fast-food restaurants, consumption of sports and energy drinks, and sugar-free, sugar-sweetened and caffeinated beverages).

Setting

Minneapolis/St. Paul metropolitan area of Minnesota (USA).

Subjects

A total of 1854 respondents (20–30 years, 55·6 % female) from the 2008–2009 survey conducted for the third wave of the population-based Project EAT (Eating and Activity in Teens and Young Adults) study.

Results

After adjustment for demographic and behavioural covariates in linear regression models, those who went to bed after 00.30 hours consumed 0·3 more servings of sugar-sweetened beverages per day, consumed 1·7 times more energy drinks, skipped breakfast 1·8 more times per week and consumed fast food 0·3 more times per week compared with those who went to bed before 22.30 hours. Reported sleep quality in the lowest (Q1)v. highest (Q3) tertile was associated with more intake of energy drinks (Q3v.Q1, prevalence ratio, 95 % CI: 1·79, 1·24, 2·34), sports drinks (1·28, 1·00, 1·55) and breakfast skipping (adjusted mean, 95 % CI: Q1: 4·03, 3·81, 4·26; Q3: 3·43, 3·17, 3·69). Time in bed and sleep variability were associated with few eating behaviours.

Conclusions

Some, but not all, sleep indices were related to problematic eating behaviours. Sleep habits may be important to address in interventions and policies that target improvements in eating patterns and health outcomes.
Predicting weight status in Chinese pre-school children: independent and interactive effects of caregiver types and feeding styles
Authors: Wei Xiaotong , Ma Yanan , Hu Jiajin , Lin Wenjing , Zhao Zhongyi , Wen Deliang
Published: December 2017

Objective

To investigate caregiver type as a potential moderating effect in the relationship between feeding style and weight status among Chinese pre-school children.

Design

Cross-sectional data collected with the Caregiver’s Feeding Style Questionnaire (CFSQ), anthropometric data, childcare and sociodemographic information.

Setting

Shenyang, China.

Subjects

Caregiver–child dyads (n 857).

Results

After controlling for confounders, authoritarian feeding style was associated with a 0·30 lower BMI Z-score. Fathers as primary caregivers were related to lower BMI Z-score (β=−0·66), while grandparents as main caregivers were associated with higher BMI Z-score (β=0·66) after adjusting for covariates. Mothers buffered the relationship between authoritarian (β=0·50, 95 % CI 0·04, 0·95) or indulgent (β=−0·60, 95 % CI −1·06, −0·14) feeding styles and BMI Z-score. Grandparents strengthened the trend that indulgent feeding style was related to higher BMI Z-score (β=0·54, 95 % CI 0·01, 1·08).

Conclusions

The results of independent and interactive effects of specific feeding styles and caregiver types had different influences on child BMI Z-scores. Longitudinal investigations are needed to evaluate the effect of fathers’ and grandparents’ feeding on their children’s nutrition and weight status.
Representation in an Era of Political and Economic Inequality: How and When Citizen Engagement Matters
Authors: Leighley Jan E. , Oser Jennifer
Published: December 2017

Does political participation make a difference for policy responsiveness, or is affluence what matters most? To examine whether participation beyond voting matters for policy representation, we analyze congruence between citizens’ policy preferences and their representatives’ roll call votes using data from the 2012 Cooperative Congressional Election Study. For the main policy issue for which citizens’ political engagement beyond voting enhances congruence—namely, the Affordable Care Act (ACA) of 2010—we then investigate whether this effect holds when taking citizens’ income into account. The findings show that for the ACA, constituents’ participation beyond voting is associated with increased congruence with their representatives at all levels of income, and that those with less income who are politically active beyond voting experience the largest increase in congruence. However, our findings also show that the potential of political participation and income to enhance congruence is restricted to co-partisans, and to highly partisan and salient issues.
The challenge of human rights for peace research
Authors: Hvidsten Andreas H. , Skarstad Kjersti
Published: December 2017

Human rights law posits a close, almost self-evident, relation between human rights and peace. Peace researchers, however, see this relation as an unsettled empirical question. In this essay, we consider the peace researchers’ (implicit) critique of human rights law. We argue that seeing the relation between human rights and peace as an empirical question rests on a largely unexamined conceptual separation of justice and peace. Re-investigating this conceptual relation reveals two positions that have different implications for human rights and peace: (1) a ‘negative’ understanding of peace as stability, and (2) a ‘positive’ understanding of peace as a working social contract. On the negative understanding, human rights may or may not be instrumentally effective in maintaining stability, which is rightly seen as an empirical question. On the positive understanding of peace, on the other hand, human rights are potentiallyconceptuallyrelated to peace, and the relation cannot be reduced to an empirical question. We argue that (2) is a better understanding of peace – at least the kind of peace envisioned in human rights philosophy – and provides a potential bridge between human rights scholarship and peace research.
Impulse response analysis of coherent waveguide communication
Authors: Kim Yanghyo , Tang Adrian , Cong Jason , Chang Mau-Chung Frank , Itoh Tatsuo
Published: December 2017

An impulse response method is carried out to analyze waveguide's information capacity within a coherent communication system. Such capability is typically estimated according to group delay variations (seconds/bandwidth/distance) after carrier-modulated data undergoes a dispersive medium. However, traditional group delay methods often ignore non-linear effects by assuming input data stream only occupies narrow bandwidth such that a propagation constant can be linearized centered at the carrier frequency. Such a constraint can be lifted with a proposed baseband equivalent impulse response method by using frequency domain convolution and multiplication. Once the impulse response in frequency domain is secured, its time domain counterpart can be calculated based on inverse Fourier transformation. Such analysis can fully reveal data pulse's broadening and gauge its inter-symbol interference by simply convolving input data with extracted impulse response, not limited to specific frequency range or type of waveguide.
Soluble Tau has devastating effects on the structural plasticity of hippocampal granule neurons
Authors: Bolós M , Pallas-Bazarra N , Terreros-Roncal J , Perea JR , Jurado-Arjona J , Ávila J , Llorens-Martín M
Published: December 2017

Tau is a neuronal microtubule-associated protein with countless physiological functions. Although the detrimental effects of insoluble aggregated Tau have been widely studied, recent evidence supports the notion that soluble Tau (composed mostly of monomers and dimers) is also toxic for neurons. Here we evaluated the long-term impact of a single stereotaxic injection of human soluble Tau on hippocampal granule neurons in mice. At the ultrastructural level, soluble Tau reduced the number of afferent synapses and caused a dramatic depletion of synaptic vesicles both in afferent and efferent synapses. Furthermore, the use of an RFP-expressing retrovirus revealed that soluble Tau altered the morphology of newborn granule neurons and reduced their afferent (dendritic spines) and efferent (mossy fiber terminals) connectivity. Finally, soluble Tau caused specific impairment of behavioral pattern separation capacity. Our results thus demonstrate for the first time that soluble Tau causes long-term detrimental effects on the morphology and connectivity of newborn granule neurons and that these effects correlate with impaired behavioral pattern separation skills. These data might be relevant for the field of neurodegenerative disorders, since they contribute to reinforcing the pathological roles played by distinct Tau species in vivo.
Gender-specific alteration of energy balance and circadian locomotor activity in the Crtc1 knockout mouse model of depression
Authors: Rossetti Clara , Sciarra Daniel , Petit Jean-Marie , Eap Chin B. , Halfon Olivier , Magistretti Pierre J. , Boutrel Benjamin , Cardinaux Jean-René
Published: December 2017

Obesity and depression are major public health concerns, and there is increasing evidence that they share etiological mechanisms. CREB-regulated transcription coactivator 1 (CRTC1) participates in neurobiological pathways involved in both mood and energy balance regulation. Crtc1−/− mice rapidly develop a depressive-like and obese phenotype in early adulthood, and are therefore a relevant animal model to explore possible common mechanisms underlying mood disorders and obesity. Here, the obese phenotype of male and female Crtc1−/− mice was further characterized by investigating CRTC1’s role in the homeostatic and hedonic regulation of food intake, as well as its influence on daily locomotor activity. Crtc1−/− mice showed a strong gender difference in the homeostatic regulation of energy balance. Mutant males were hyperphagic and rapidly developed obesity on normal chow diet, whereas Crtc1−/− females exhibited mild late-onset obesity without hyperphagia. Overeating of mutant males was accompanied by alterations in the expression of several orexigenic and anorexigenic hypothalamic genes, thus confirming a key role of CRTC1 in the central regulation of food intake. No alteration in preference and conditioned response for saccharine was observed in Crtc1−
/−
mice, suggesting that mutant males’ hyperphagia was not due to an altered hedonic regulation of food intake. Intriguingly, mutant males exhibited a hyperphagic behavior only during the resting (diurnal) phase of the light cycle. This abnormal feeding behavior was associated with a higher diurnal locomotor activity indicating that the lack of CRTC1 may affect circadian rhythmicity. Collectively, these findings highlight the male-specific involvement of CRTC1 in the central control of energy balance and circadian locomotor activity.
Bayesian prediction intervals for assessing P-value variability in prospective replication studies
Authors: Vsevolozhskaya Olga , Ruiz Gabriel , Zaykin Dmitri
Published: December 2017

Increased availability of data and accessibility of computational tools in recent years have created an unprecedented upsurge of scientific studies driven by statistical analysis. Limitations inherent to statistics impose constraints on the reliability of conclusions drawn from data, so misuse of statistical methods is a growing concern. Hypothesis and significance testing, and the accompanying P-values are being scrutinized as representing the most widely applied and abused practices. One line of critique is that P-values are inherently unfit to fulfill their ostensible role as measures of credibility for scientific hypotheses. It has also been suggested that while P-values may have their role as summary measures of effect, researchers underappreciate the degree of randomness in the P-value. High variability of P-values would suggest that having obtained a small P-value in one study, one is, ne vertheless, still likely to obtain a much larger P-value in a similarly powered replication study. Thus, “replicability of P-value” is in itself questionable. To characterize P-value variability, one can use prediction intervals whose endpoints reflect the likely spread of P-values that could have been obtained by a replication study. Unfortunately, the intervals currently in use, the frequentist P-intervals, are based on unrealistic implicit assumptions. Namely, P-intervals are constructed with the assumptions that imply substantial chances of encountering large values of effect size in an observational study, which leads to bias. The long-run frequentist probability provided by P-intervals is similar in interpretation to that of the classical confidence intervals, but the endpoints of any particular interval lack interpretation as probabilistic bounds for the possible spread of future P-values that may have been obtained in replication studies. Along with classical frequentist intervals, there exists a Bayesian viewpoint toward interval construction in which the endpoints of an interval have a meaningful probabilistic interpretation. We propose Bayesian intervals for prediction of P-value variability in prospective replication studies. Contingent upon approximate prior knowledge of the effect size distribution, our proposed Bayesian intervals have endpoints that are directly interpretable as probabilistic bounds for replication P-values, and they are resistant to selection bias. We showcase our approach by its application to P-values reported for five psychiatric disorders by the Psychiatric Genomics Consortium group.
Association between serum neuron-specific enolase, age, overweight, and structural MRI patterns in 901 subjects
Authors: Hoffmann Johanna , Janowitz Deborah , Van der Auwera Sandra , Wittfeld Katharina , Nauck Matthias , Friedrich Nele , Habes Mohamad , Davatzikos Christos , Terock Jan , Bahls Martin , Goltz Annemarie , Kuhla Angela , Völzke Henry , Jörgen Grabe Hans
Published: December 2017

Serum neuron-specific enolase (sNSE) is considered a marker for neuronal damage, related to gray matter structures. Previous studies indicated its potential as marker for structural and functional damage in conditions with adverse effects to the brain like obesity and dementia. In the present study, we investigated the putative association between sNSE levels, body mass index (BMI), total gray matter volume (GMV), and magnetic resonance imaging-based indices of aging as well as Alzheimer’s disease (AD)-like patterns. Subjects/Methods: sNSE was determined in 901 subjects (499 women, 22–81 years, BMI 18–48 kg/m2), participating in a population-based study (SHIP-TREND). We report age-specific patterns of sNSE levels between males and females. Females showed augmenting, males decreasing sNSE levels associated with age (males: p = 0.1052, females: p = 0.0363). sNSE levels and BMI were non-linearly associated, showing a parabolic association and decreasing sNSE levels at BMI values >25 (p = 0.0056). In contrast to our hypotheses, sNSE levels were not associated with total GMV, aging, or AD-like patterns. Pathomechanisms discussed are: sex-specific hormonal differences, neuronal damage/differentiation, or impaired cerebral glucose metabolism. We assume a sex-dependence of age-related effects to the brain. Further, we propose in accordance to previous studies an actual neuronal damage in the early stages of obesity. However, with progression of overweight, we assume more profound effects of excess body fat to the brain.
Complement C3a signaling facilitates skeletal muscle regeneration by regulating monocyte function and trafficking
Authors: Zhang Congcong , Wang Chunxiao , Li Yulin , Miwa Takashi , Liu Chang , Cui Wei , Song Wen-Chao , Du Jie
Published: December 2017

Regeneration of skeletal muscle following injury is accompanied by transient inflammation. Here we show that complement is activated in skeletal muscle injury and plays a key role during regeneration. Genetic ablation of complement C3 or its inactivation with Cobra Venom Factor (CVF) result in impaired muscle regeneration following cardiotoxin-induced injury in mice. The effect of complement in muscle regeneration is mediated by the alternative pathway and C3a receptor (C3aR) signaling, as deletion of Cfb, a key alternative pathway component, or C3aR leads to impaired regeneration and reduced monocyte/macrophage infiltration. Monocytes from C3aR-deficient mice express a reduced level of adhesion molecules, cytokines and genes associated with antigen processing and presentation. Exogenous administration of recombinant CCL5 to C3aR-deficient mice rescues the defects in inflammatory cell recruitment and regeneration. These findings reveal an important role of complement C3a in skeletal muscle regeneration, and suggest that manipulating complement system may produce therapeutic benefit in muscle injury and regeneration.
Lipoteichoic acid deficiency permits normal growth but impairs virulence of Streptococcus pneumoniae
Authors: Heß Nathalie , Waldow Franziska , Kohler Thomas P. , Rohde Manfred , Kreikemeyer Bernd , Gómez-Mejia Alejandro , Hain Torsten , Schwudke Dominik , Vollmer Waldemar , Hammerschmidt Sven , Gisch Nicolas
Published: December 2017

Teichoic acid (TA), a crucial cell wall constituent of the pathobiontStreptococcus pneumoniae, is bound to peptidoglycan (wall teichoic acid, WTA) or to membrane glycolipids (lipoteichoic acid, LTA). Both TA polymers share a common precursor synthesis pathway, but differ in the final transfer of the TA chain to either peptidoglycan or a glycolipid. Here, we show that LTA exhibits a different linkage conformation compared to WTA, and identify TacL (previously known as RafX) as a putative lipoteichoic acid ligase required for LTA assembly. Pneumococcal mutants deficient in TacL lack LTA and show attenuated virulence in mouse models of acute pneumonia and systemic infections, although they grow normally in culture. Hence, LTA is important forS. pneumoniaeto establish systemic infections, and TacL represents a potential target for antimicrobial drug development.
Round complexity in the local transformations of quantum and classical states
Authors: Chitambar Eric , Hsieh Min-Hsiu
Published: December 2017

In distributed quantum and classical information processing, spatially separated parties operate locally on their respective subsystems, but coordinate their actions through multiple exchanges of public communication. With interaction, the parties can perform more tasks. But how the exact number and order of exchanges enhances their operational capabilities is not well understood. Here we consider the minimum number of communication rounds needed to perform the locality-constrained tasks of entanglement transformation and its classical analog of secrecy manipulation. We provide an explicit construction of both quantum and classical state transformations which, for any given r, can be achieved using r rounds of classical communication exchanges, but no fewer. To show this, we build on the common structure underlying both resource theories of quantum entanglement and classical secret key. Our results reveal that highly complex communication protocols are indeed necessary to fully harness the information-theoretic resources contained in general quantum and classical states.
Dynamical trade-offs arise from antagonistic coevolution and decrease intraspecific diversity
Authors: Huang Weini , Traulsen Arne , Werner Benjamin , Hiltunen Teppo , Becks Lutz
Published: December 2017

Trade-offs play an important role in evolution. Without trade-offs, evolution would maximize fitness of all traits leading to a “master of all traits”. The shape of trade-offs has been shown to determine evolutionary trajectories and is often assumed to be static and independent of the actual evolutionary process. Here we propose that coevolution leads to a dynamical trade-off. We test this hypothesis in a microbial predator–prey system and show that the bacterial growth-defense trade-off changes from concave to convex, i.e., defense is effective and cheap initially, but gets costly when predators coevolve. We further explore the impact of such dynamical trade-offs by a novel mathematical model incorporating de novo mutations for both species. Predator and prey populations diversify rapidly leading to higher prey diversity when the trade-off is concave (cheap). Coevolution results in more convex (costly) trade-offs and lower prey diversity compared to the scenario where only the prey evolves.
Coupling between oxygen redox and cation migration explains unusual electrochemistry in lithium-rich layered oxides
Authors: Gent William E. , Lim Kipil , Liang Yufeng , Li Qinghao , Barnes Taylor , Ahn Sung-Jin , Stone Kevin H. , McIntire Mitchell , Hong Jihyun , Song Jay Hyok , Li Yiyang , Mehta Apurva , Ermon Stefano , Tyliszczak Tolek , Kilcoyne David , Vine David , Park Jin-Hwan , Doo Seok-Kwang , Toney Michael F. , Yang Wanli , Prendergast David , Chueh William C.
Published: December 2017

Lithium-rich layered transition metal oxide positive electrodes offer access to anion redox at high potentials, thereby promising high energy densities for lithium-ion batteries. However, anion redox is also associated with several unfavorable electrochemical properties, such as open-circuit voltage hysteresis. Here we reveal that in Li1.17–x
Ni0.21Co0.08Mn0.54O2, these properties arise from a strong coupling between anion redox and cation migration. We combine various X-ray spectroscopic, microscopic, and structural probes to show that partially reversible transition metal migration decreases the potential of the bulk oxygen redox couple by > 1 V, leading to a reordering in the anionic and cationic redox potentials during cycling. First principles calculations show that this is due to the drastic change in the local oxygen coordination environments associated with the transition metal migration. We propose that this mechanism is involved in stabilizing the oxygen redox couple, which we observe spectroscopically to persist for 500 charge/discharge cycles.
Evolution of a flipped pathway creates metabolic innovation in tomato trichomes through BAHD enzyme promiscuity
Authors: Fan Pengxiang , Miller Abigail M. , Liu Xiaoxiao , Jones A. Daniel , Last Robert L.
Published: December 2017

Plants produce hundreds of thousands of structurally diverse specialized metabolites via multistep biosynthetic networks, including compounds of ecological and therapeutic importance. These pathways are restricted to specific plant groups, and are excellent systems for understanding metabolic evolution. Tomato and other plants in the nightshade family synthesize protective acylated sugars in the tip cells of glandular trichomes on stems and leaves. We describe a metabolic innovation in wild tomato species that contributes to acylsucrose structural diversity. A small number of amino acid changes in two acylsucrose acyltransferases alter their acyl acceptor preferences, resulting in reversal of their order of reaction and increased product diversity. This study demonstrates how small numbers of amino acid changes in multiple pathway enzymes can lead to diversification of specialized metabolites in plants. It also highlights the power of a combined genetic, genomic and in vitro biochemical approach to identify the evolutionary mechanisms leading to metabolic novelty.
Multinational patterns of seasonal asymmetry in human movement influence infectious disease dynamics
Authors: Wesolowski Amy , zu Erbach-Schoenberg Elisabeth , Tatem Andrew J. , Lourenço Christopher , Viboud Cecile , Charu Vivek , Eagle Nathan , Engø-Monsen Kenth , Qureshi Taimur , Buckee Caroline O. , Metcalf C. J. E.
Published: December 2017

Seasonal variation in human mobility is globally ubiquitous and affects the spatial spread of infectious diseases, but the ability to measure seasonality in human movement has been limited by data availability. Here, we use mobile phone data to quantify seasonal travel and directional asymmetries in Kenya, Namibia, and Pakistan, across a spectrum from rural nomadic populations to highly urbanized communities. We then model how the geographic spread of several acute pathogens with varying life histories could depend on country-wide connectivity fluctuations through the year. In all three countries, major national holidays are associated with shifts in the scope of travel. Within this broader pattern, the relative importance of particular routes also fluctuates over the course of the year, with increased travel from rural to urban communities after national holidays, for example. These changes in travel impact how fast communities are likely to be reached by an introduced pathogen.
PEPD is a pivotal regulator of p53 tumor suppressor
Authors: Yang Lu , Li Yun , Bhattacharya Arup , Zhang Yuesheng
Published: December 2017

p53 tumor suppressor responds to various cellular stresses and regulates cell fate. Here, we show that peptidase D (PEPD) binds and suppresses over half of nuclear and cytoplasmic p53 under normal conditions, independent of its enzymatic activity. Eliminating PEPD causes cell death and tumor regression due to p53 activation. PEPD binds to the proline-rich domain in p53, which inhibits phosphorylation of nuclear p53 and MDM2-mediated mitochondrial translocation of nuclear and cytoplasmic p53. However, the PEPD-p53 complex is critical for p53 response to stress, as stress signals doxorubicin and H2O2 each must free p53 from PEPD in order to achieve robust p53 activation, which is mediated by reactive oxygen species. Thus, PEPD stores p53 for the stress response, but this also renders cells dependent on PEPD for survival, as it suppresses p53. This finding provides further understanding of p53 regulation and may have significant implications for the treatment of cancer and other diseases.
Prodigious submarine landslides during the inception and early growth of volcanic islands
Authors: Hunt James E. , Jarvis Ian
Published: December 2017

Volcanic island inception applies large stresses as the ocean crust domes in response to magma ascension and is loaded by eruption of lavas. There is currently limited information on when volcanic islands are initiated on the seafloor, and no information regarding the seafloor instabilities island inception may cause. The deep sea Madeira Abyssal Plain contains a 43 million year history of turbidites among which many originate from mass movements in the Canary Islands. Here, we investigate the composition and timing of a distinctive group of turbidites that we suggest represent a new unique record of large-volume submarine landslides triggered during the inception, submarine shield growth, and final subaerial emergence of the Canary Islands. These slides are predominantly multi-stage and yet represent among the largest mass movements on the Earth’s surface up to three or more-times larger than subaerial Canary Islands flank collapses. Thus whilst these deposits provide invaluable information on ocean island geodynamics they also represent a significant, and as yet unaccounted, marine geohazard.
Comprehensive phase diagram of two-dimensional space charge doped Bi2Sr2CaCu2O8+x
Authors: Sterpetti Edoardo , Biscaras Johan , Erb Andreas , Shukla Abhay
Published: December 2017

The phase diagram of hole-doped high critical temperature superconductors as a function of doping and temperature has been intensively studied with chemical variation of doping. Chemical doping can provoke structural changes and disorder, masking intrinsic effects. Alternatively, a field-effect transistor geometry with an electrostatically doped, ultra-thin sample can be used. However, to probe the phase diagram, carrier density modulation beyond 1014 cm−2 and transport measurements performed over a large temperature range are needed. Here we use the space charge doping method to measure transport characteristics from 330 K to low temperature. We extract parameters and characteristic temperatures over a large doping range and establish a comprehensive phase diagram for one-unit-cell-thick BSCCO-2212 as a function of doping, temperature and disorder.
Global unleashing of transcription elongation waves in response to genotoxic stress restricts somatic mutation rate
Authors: Lavigne Matthieu D. , Konstantopoulos Dimitris , Ntakou-Zamplara Katerina Z. , Liakos Anastasios , Fousteri Maria
Published: December 2017

Complex molecular responses preserve gene expression accuracy and genome integrity in the face of environmental perturbations. Here we report that, in response to UV irradiation, RNA polymerase II (RNAPII) molecules are dynamically and synchronously released from promoter-proximal regions into elongation to promote uniform and accelerated surveillance of the whole transcribed genome. The maximised influx of de novo released RNAPII correlates with increased damage-sensing, as confirmed by RNAPII progressive accumulation at dipyrimidine sites and by the average slow-down of elongation rates in gene bodies. In turn, this transcription elongation ‘safe’ mode guarantees efficient DNA repair regardless of damage location, gene size and transcription level. Accordingly, we detect low and homogenous rates of mutational signatures associated with UV exposure or cigarette smoke across all active genes. Our study reveals a novel advantage for transcription regulation at the promoter-proximal level and provides unanticipated insights into how active transcription shapes the mutagenic landscape of cancer genomes.
Balancing mcr-1 expression and bacterial survival is a delicate equilibrium between essential cellular defence mechanisms
Authors: Yang Qiue , Li Mei , Spiller Owen B. , Andrey Diego O. , Hinchliffe Philip , Li Hui , MacLean Craig , Niumsup Pannika , Powell Lydia , Pritchard Manon , Papkou Andrei , Shen Yingbo , Portal Edward , Sands Kirsty , Spencer James , Tansawai Uttapoln , Thomas David , Wang Shaolin , Wang Yang , Shen Jianzhong , Walsh Timothy
Published: December 2017

MCR-1 is a lipid A modifying enzyme that confers resistance to the antibiotic colistin. Here, we analyse the impact of MCR-1 expression on E. coli morphology, fitness, competitiveness, immune stimulation and virulence. Increased expression of mcr-1 results in decreased growth rate, cell viability, competitive ability and significant degradation in cell membrane and cytoplasmic structures, compared to expression of catalytically inactive MCR-1 (E246A) or MCR-1 soluble component. Lipopolysaccharide (LPS) extracted from mcr-1 strains induces lower production of IL-6 and TNF, when compared to control LPS. Compared to their parent strains, high-level colistin resistance mutants (HLCRMs) show reduced fitness (relative fitness is 0.41–0.78) and highly attenuated virulence in a Galleria mellonella infection model. Furthermore, HLCRMs are more susceptible to most antibiotics than their respective parent strains. Our results show that the bacterium is challenged to find a delicate equilibrium between expression of MCR-1-mediated colistin resistance and minimalizing toxicity and thus ensuring cell survival.
Identification and characterization of two functional variants in the human longevity gene FOXO3
Authors: Flachsbart Friederike , Dose Janina , Gentschew Liljana , Geismann Claudia , Caliebe Amke , Knecht Carolin , Nygaard Marianne , Badarinarayan Nandini , ElSharawy Abdou , May Sandra , Luzius Anne , Torres Guillermo G. , Jentzsch Marlene , Forster Michael , Häsler Robert , Pallauf Kathrin , Lieb Wolfgang , Derbois Céline , Galan Pilar , Drichel Dmitriy , Arlt Alexander , Till Andreas , Krause-Kyora Ben , Rimbach Gerald , Blanché Hélène , Deleuze Jean-François , Christiansen Lene , Christensen Kaare , Nothnagel Michael , Rosenstiel Philip , Schreiber Stefan , Franke Andre , Sebens Susanne , Nebel Almut
Published: December 2017

FOXO3 is consistently annotated as a human longevity gene. However, functional variants and underlying mechanisms for the association remain unknown. Here, we perform resequencing of the FOXO3 locus and single-nucleotide variant (SNV) genotyping in three European populations. We find two FOXO3 SNVs, rs12206094 and rs4946935, to be most significantly associated with longevity and further characterize them functionally. We experimentally validate the in silico predicted allele-dependent binding of transcription factors (CTCF, SRF) to the SNVs. Specifically, in luciferase reporter assays, the longevity alleles of both variants show considerable enhancer activities that are reversed by IGF-1 treatment. An eQTL database search reveals that the alleles are also associated with higher FOXO3 mRNA expression in various human tissues, which is in line with observations in long-lived model organisms. In summary, we present experimental evidence for a functional link between common intronic variants in FOXO3 and human longevity.
Mating system manipulation and the evolution of sex-biased gene expression in Drosophila
Authors: Veltsos Paris , Fang Yongxiang , Cossins Andrew R. , Snook Rhonda R. , Ritchie Michael G.
Published: December 2017

Sex differences in dioecious animals are pervasive and result from gene expression differences. Elevated sexual selection has been predicted to increase the number and expression of male-biased genes, and experimentally imposing monogamy onDrosophila melanogasterhas led to a relative feminisation of the transcriptome. Here, we test this hypothesis further by subjecting another polyandrous species,D. pseudoobscura, to 150 generations of experimental monogamy or elevated polyandry. We find that sex-biased genes do change in expression but, contrary to predictions, there is usually masculinisation of the transcriptome under monogamy, although this depends on tissue and sex. We also identify and describe gene expression changes following courtship experience. Courtship often influences gene expression, including patterns in sex-biased gene expression. Our results confirm that mating system manipulation disproportionately influences sex-biased gene expression but show that the direction of change is dynamic and unpredictable.
An oomycete plant pathogen reprograms host pre-mRNA splicing to subvert immunity
Authors: Huang Jie , Gu Lianfeng , Zhang Ying , Yan Tingxiu , Kong Guanghui , Kong Liang , Guo Baodian , Qiu Min , Wang Yang , Jing Maofeng , Xing Weiman , Ye Wenwu , Wu Zhe , Zhang Zhengguang , Zheng Xiaobo , Gijzen Mark , Wang Yuanchao , Dong Suomeng
Published: December 2017

The process of RNA splicing influences many physiological processes, including plant immunity. However, how plant parasites manipulate host RNA splicing process remains unknown. Here we demonstrate that PsAvr3c, an avirulence effector from oomycete plant pathogen Phytophthora sojae, physically binds to and stabilizes soybean serine/lysine/arginine-rich proteins GmSKRPs. The SKRPs are novel proteins that associate with a complex that contains plant spliceosome components, and are negative regulators of plant immunity. Analysis by RNA-seq data indicates that alternative splicing of pre-mRNAs from 401 soybean genes, including defense-related genes, is altered in GmSKRP1 and PsAvr3c overexpressing lines compared to control plants. Representative splicing events mediated by GmSKRP1 and PsAvr3c are tested by infection assays or by transient expression in soybean plants. Our results show that plant pathogen effectors can reprogram host pre-mRNA splicing to promote disease, and we propose that pathogens evolved such strategies to defeat host immune systems.
Controlling supercurrents and their spatial distribution in ferromagnets
Authors: Lahabi Kaveh , Amundsen Morten , Ouassou Jabir Ali , Beukers Ewout , Pleijster Menno , Linder Jacob , Alkemade Paul , Aarts Jan
Published: December 2017

Spin-triplet Cooper pairs induced in ferromagnets form the centrepiece of the emerging field of superconducting spintronics. Usually the focus is on the spin-polarization of the triplets, potentially enabling low-dissipation magnetization switching. However, the magnetic texture which provides the fundamental mechanism for generating triplets also permits control over the spatial distribution of supercurrent. Here we demonstrate the tailoring of distinct supercurrent pathways in the ferromagnetic barrier of a Josephson junction. We combine micromagnetic simulations with three-dimensional supercurrent calculations to design a disk-shaped structure with a ferromagnetic vortex which induces two transport channels across the junction. By using superconducting quantum interferometry, we show the existence of two channels. Moreover, we show how the supercurrent can be controlled by moving the vortex with a magnetic field. This approach paves the way for supercurrent paths to be dynamically reconfigured in order to switch between different functionalities in the same device.
Voltage-gated sodium channels assemble and gate as dimers
Authors: Clatot Jérôme , Hoshi Malcolm , Wan Xiaoping , Liu Haiyan , Jain Ankur , Shinlapawittayatorn Krekwit , Marionneau Céline , Ficker Eckhard , Ha Taekjip , Deschênes Isabelle
Published: December 2017

Fast opening and closing of voltage-gated sodium channels are crucial for proper propagation of the action potential through excitable tissues. Unlike potassium channels, sodium channel α-subunits are believed to form functional monomers. Yet, an increasing body of literature shows inconsistency with the traditional idea of a single α-subunit functioning as a monomer. Here we demonstrate that sodium channel α-subunits not only physically interact with each other but they actually assemble, function and gate as a dimer. We identify the region involved in the dimerization and demonstrate that 14-3-3 protein mediates the coupled gating. Importantly we show conservation of this mechanism among mammalian sodium channels. Our study not only shifts conventional paradigms in regard to sodium channel assembly, structure, and function but importantly this discovery of the mechanism involved in channel dimerization and biophysical coupling could open the door to new approaches and targets to treat and/or prevent sodium channelopathies.
p16Ink4a and p21Cip1/Waf1 promote tumour growth by enhancing myeloid-derived suppressor cells chemotaxis
Authors: Okuma Atsushi , Hanyu Aki , Watanabe Sugiko , Hara Eiji
Published: December 2017

p16Ink4aand p21Cip1/Waf1act as tumour suppressors through induction of cellular senescence. However, senescence-independent roles of these CDK inhibitors are not well understood. Here, we report an unexpected function of p16Ink4and p21Cip1/Waf1, namely, tumour promotion through chemotaxis. In monocytic myeloid-derived suppressor cells (Mo-MDSCs), p16Ink4and p21Cip1/Waf1are highly expressed and stimulate CX3CR1 chemokine receptor expression by preventing CDK-mediated phosphorylation and inactivation of SMAD3. Thus, deletion ofp16Ink4andp21Cip1/Waf1reduces CX3CR1 expression, thereby inhibiting Mo-MDSC accumulation in tumours expressing CX3CL1 and suppressing the tumour progression in mice. Notably, blockade of the CX3CL1/CX3CR1 axis suppresses tumour growth, whereas inactivation of CDKs elicits the opposite effect. These findings reveal an unexpected function ofp16Ink4aandp21Waf1/Cip1and indicate that regulation of Mo-MDSCs chemotaxis is a valuable potential strategy for control of tumour development.
Forming quasicrystals by monodisperse soft core particles
Authors: Zu Mengjie , Tan Peng , Xu Ning
Published: December 2017

In traditional approaches to form quasicrystals, multiple competing length scales involved in particle size, shape, or interaction potential are believed to be necessary. It is unexpected that quasicrystals can be formed by monodisperse, isotropic particles interacting via a simple potential that does not contain explicit multiple length scales to stabilize quasicrystals. Here, we report the surprising finding of the formation of such quasicrystals in high-density systems of soft-core particles. Although there are length scales naturally introduced in our model systems, they do not establish the quasicrystalline order. In two dimensions, we find not only dodecagonal but also octagonal quasicrystals, which have not been found yet in soft quasicrystals. In such unexpected quasicrystals, particles tend to form pentagons, which are essential elements to develop the quasicrystalline order. Our findings thus pave an unexpected and simple way to form quasicrystals and pose a challenge for theoretical understanding of quasicrystals.
High-Resolution Single Particle Zeta Potential Characterisation of Biological Nanoparticles using Tunable Resistive Pulse Sensing
Authors: Vogel Robert , Pal Anoop K. , Jambhrunkar Siddharth , Patel Pragnesh , Thakur Sachin S. , Reátegui Eduardo , Parekh Harendra S. , Saá Paula , Stassinopoulos Adonis , Broom Murray F.
Published: December 2017

Physicochemical properties of nanoparticles, such as size, shape, surface charge, density, and porosity play a central role in biological interactions and hence accurate determination of these characteristics is of utmost importance. Here we propose tunable resistive pulse sensing for simultaneous size and surface charge measurements on a particle-by-particle basis, enabling the analysis of a wide spectrum of nanoparticles and their mixtures. Existing methodologies for measuring zeta potential of nanoparticles using resistive pulse sensing are significantly improved by including convection into the theoretical model. The efficacy of this methodology is demonstrated for a range of biological case studies, including measurements of mixed anionic, cationic liposomes, extracellular vesicles in plasma, and in situ time study of DNA immobilisation on the surface of magnetic nanoparticles. The high-resolution single particle size and zeta potential characterisation will provide a better understanding of nano-bio interactions, positively impacting nanomedicine development and their regulatory approval.
The Differentiation Stage of Transplanted Stem Cells Modulates Nerve Regeneration
Authors: Huang Ching-Wen , Huang Wen-Chin , Qiu Xuefeng , Fernandes Ferreira da Silva Flavia , Wang Aijun , Patel Shyam , Nesti Leon J. , Poo Mu-Ming , Li Song
Published: December 2017

In regenerative medicine applications, the differentiation stage of implanted stem cells must be optimized to control cell fate and enhance therapeutic efficacy. We investigated the therapeutic potential of human induced pluripotent stem cell (iPSC)-derived cells at two differentiation stages on peripheral nerve regeneration. Neural crest stem cells (NCSCs) and Schwann cells (NCSC-SCs) derived from iPSCs were used to construct a tissue-engineered nerve conduit that was applied to bridge injured nerves in a rat sciatic nerve transection model. Upon nerve conduit implantation, the NCSC group showed significantly higher electrophysiological recovery at 1 month as well as better gastrocnemius muscle recovery at 5 months than the acellular group, but the NCSC-SC group didn’t. Both transplanted NCSCs and NCSC-SCs interacted with newly-growing host axons, while NCSCs showed better survival rate and distribution. The transplanted NCSCs mainly differentiated into Schwann cells with no teratoma formation, and they secreted higher concentrations of brain-derived neurotrophic factor and nerve growth factor than NCSC-SCs. In conclusion, transplantation of iPSC-NCSCs accelerated functional nerve recovery with the involvement of stem cell differentiation and paracrine signaling. This study unravels thein vivoperformance of stem cells during tissue regeneration, and provides a rationale of using appropriate stem cells for regenerative medicine.
From Discovery to Translation: Characterization of C-Mannosyltryptophan and Pseudouridine as Markers of Kidney Function
Authors: Sekula Peggy , Dettmer Katja , Vogl Franziska C. , Gronwald Wolfram , Ellmann Lisa , Mohney Robert P. , Eckardt Kai-Uwe , Suhre Karsten , Kastenmüller Gabi , Oefner Peter J. , Köttgen Anna
Published: December 2017

Using a non-targeted metabolomics platform, we recently identified C-mannosyltryptophan and pseudouridine as non-traditional kidney function markers. The aims of this study were to obtain absolute concentrations of both metabolites in blood and urine from individuals with and without CKD to provide reference ranges and to assess their fractional excretions (FE), and to assess the agreement with their non-targeted counterparts. In individuals without/with CKD, mean plasma and urine concentrations for C-mannosyltryptophan were 0.26/0.72 µmol/L and 3.39/4.30 µmol/mmol creatinine, respectively. The respective concentrations for pseudouridine were 2.89/5.67 µmol/L and 39.7/33.9 µmol/mmol creatinine. Median (25th, 75th percentiles) FEs were 70.8% (65.6%, 77.8%) for C-mannosyltryptophan and 76.0% (68.6%, 82.4%) for pseudouridine, indicating partial net reabsorption. Association analyses validated reported associations between single metabolites and eGFR. Targeted measurements of both metabolites agreed well with the non-targeted measurements, especially in urine. Agreement for composite nephrological measures FE and urinary metabolite-to-creatinine ratio was lower, but could be improved by replacing non-targeted creatinine measurements with a standard clinical creatinine test. In summary, targeted quantification and additional characterization in relevant populations are necessary steps in the translation of non-traditional biomarkers in nephrology from non-targeted discovery to clinical application.
Revisiting unexploited antibiotics in search of new antibacterial drug candidates: the case of γ-actinorhodin
Authors: Nass Nada M. , Farooque Sannia , Hind Charlotte , Wand Matthew E. , Randall Christopher P. , Sutton J. Mark , Seipke Ryan F. , Rayner Christopher M. , O’Neill Alex J.
Published: December 2017

Of the thousands of natural product antibiotics discovered to date, only a handful have been developed for the treatment of bacterial infection. The clinically unexploited majority likely include compounds with untapped potential as antibacterial drugs, and in view of the ever-growing unmet medical need for such agents, warrant systematic re-evaluation. Here we revisit the actinorhodins, a class that was first reported 70 years ago, but which remains poorly characterized. We show that γ-actinorhodin possesses many of the requisite properties of an antibacterial drug, displaying potent and selective bactericidal activity against key Gram-positive pathogens (including Staphylococcus aureus and enterococci), a mode of action distinct from that of other agents in clinical use, an extremely low potential for the development of resistance, and a degree of in vivo efficacy in an invertebrate model of infection. Our findings underscore the utility of revisiting unexploited antibiotics as a source of novel antibacterial drug candidates.
Relation of Ultrasound Findings and Abdominal Symptoms obtained with the CFAbd-Score in Cystic Fibrosis Patients
Authors: Tabori Harold , Jaudszus Anke , Arnold Christin , Mentzel Hans-Joachim , Lorenz Michael , Michl Ruth K. , Lehmann Thomas , Renz Diane M. , Mainz Jochen G.
Published: December 2017

Abdominal symptoms are a hallmark of Cystic fibrosis (CF). Yet, their association with morphological abnormalities of different abdominal organs is still poorly understood. Aim was therefore to relate these symptoms, assessed with a questionnaire, to findings in abdominal ultrasound (US). In 114 CF patients of all ages, findings in US considering seventeen specific parameters were related to abdominal symptoms compiled with our novel CF-specific 26-modal symptom score (CFAbd-Score). US abnormalities were detected in 95% of the patients. Most frequent findings were pancreatic lipomatosis (88%), liver steatosis (37%), hepatomegaly (31%), and thickened bowel walls (23%). Highest burden of GI-symptoms was clearly associated with pancreatic lipomatosis (p = 0.036). In detail, patients revealing this pathology reported higher rates of abdominal pain (p = 0.018), flatulence (p = 0.006), heartburn (p = 0.04), and reflux of stomach content (p = 0.006). Patients with pancreatic sufficiency had less US-findings (p = 0.033), which in turn was associated with lower rates of abdominal symptoms. The majority of them were carriers of class IV-VI or G551D mutations. Our approach gives new insights regarding the underestimated multi-organ abdominal involvement in CF. The new score can be of high interest e.g. as a complementary tool to assess the gastrointestinal effects of promising novel CF therapeutics.