bluuebunny/crossref_metadata_2025 huggingface dataset:
Three or More Courses of Stereotactic Radiosurgery for Patients with Multiply Recurrent Brain Metastases
Authors: Kotecha Rupesh , Damico Nicholas , Miller Jacob A. , Suh John H. , Murphy Erin S. , Reddy Chandana A. , Barnett Gene H. , Vogelbaum Michael A. , Angelov Lilyana , Mohammadi Alireza M. , Chao Samuel T.
Published: February 2017

BACKGROUND: Although patients with brain metastasis are treated with primary stereotactic radiosurgery (SRS), the use of salvage therapies and their consequence remains understudied.

OBJECTIVE: To study the intracranial recurrence patterns and salvage therapies for patients who underwent multiple SRS courses.

METHODS: A retrospective review was performed of 59 patients with brain metastases who underwent ≥3 SRS courses for new lesions. Cox regression analyzed factors predictive for overall survival.

RESULTS: The median age at diagnosis was 52 years. Over time, patients underwent a median of 3 courses of SRS (range: 3-8) to a total of 765 different brain metastases. The 6-month risk of distant intracranial recurrence after the first SRS treatment was 64% (95% confidence interval: 52%-77%). Overall survival was 40% (95% confidence interval: 28%-53%) at 24 months. Only 24 patients (41%) had a decline in their Karnofsky Performance Status ≤70 at last office visit. Quality of life was preserved among 77% of patients at 12 months, with 45% experiencing clinically significant improvement during clinical follow-up. Radiation necrosis developed in 10 patients (17%). On multivariate analysis, gender (males, Hazard Ratio [HR]: 2.0, P < .05), Karnofsky Performance Status ≤80 (HR 3.2, P < .001), extracranial metastases (HR: 3.6, P < .001), and a distant intracranial recurrence ≤3 months from initial to repeat SRS (HR: 3.8, P < .001) were associated with a poorer survival.

CONCLUSION: In selected patients, performing ≥3 SRS courses controls intracranial disease. Patients may need salvage SRS for distant intracranial relapse, but focal retreatments are associated with modest toxicity, do not appear to negatively affect a patient's performance status, and help preserve quality of life.
Importance and Difficulties of Pursuing rTMS Research in Acute Stroke
Authors: Carey James R. , Chappuis Diane M. , Finkelstein Marsha J. , Frost Kate L. , Leuty Lynette K. , McNulty Allison L. , Oddsson Lars I. E. , Seifert Erin M. , Kimberley Teresa J.
Published: February 2017

Although much research has been done on repetitive transcranial magnetic stimulation (rTMS) in chronic stroke, only sparse research has been done in acute stroke despite the particularly rich potential for neuroplasticity in this stage. We attempted a preliminary clinical trial in one active, high-quality inpatient rehabilitation facility (IRF) in the -United States. But after enrolling only 4 patients in the grant period, the study was stopped because of low enrollment. The purpose of this paper is to offer a perspective describing the important physiologic rationale for including rTMS in the early phase of stroke, the reasons for our poor patient enrollment in our attempted study, and recommendations to help future studies succeed. We conclude that, if scientists and clinicians hope to enhance stroke outcomes, more attention must be directed to leveraging conventional rehabilitation with neuromodulation in the acute phase of stroke when the capacity for neuroplasticity is optimal. Difficulties with patient enrollment must be addressed by reassessing traditional inclusion and exclusion criteria. Factors that shorten patients’ length of stay in the IRF must also be reassessed at all policy-making levels to make ethical decisions that promote higher functional outcomes while retaining cost consciousness.
Persistent homology: a tool to universally measure plant morphologies across organs and scales
Authors: Li Mao , Frank Margaret H. , Coneva Viktoriya , Mio Washington , Topp Christopher N. , Chitwood Daniel H.
Published: February 2017

Genetic contributions to plant morphology are not partitioned between shoots and roots. Yet, shoot and root architectures are rarely measured in the same plants. Even if shoot and root architectures are both studied, the application of mathematical methods flexible enough to accommodate the disparate topologies and shapes within a plant, and across scales, are lacking. Here, we advocate the use of persistent homology, a mathematical method robust to noise, invariant with respect to orientation, capable of application across diverse scales, and importantly, compatible with diverse functions to quantify disparate plant morphologies, architectures, and textures. To demonstrate the usefulness of this method, we apply persistent homology approaches to the shape of leaves, serrations, and root architecture as measured in the same plants of a domesticated tomato Solanum pennellii near-isogenic introgression line population under field conditions. We find that genetic contributions to morphology affect the plant in a concerted fashion, affecting both the shoot and root, revealing a pleiotropic basis to natural variation in tomato.
Multiple introductions of Zika virus into the United States revealed through genomic epidemiology
Authors: Grubaugh Nathan D , Ladner Jason T , Kraemer Moritz UG , Dudas Gytis , Tan Amanda L , Gangavarapu Karthik , Wiley Michael R , White Stephen , Thézé Julien , Magnani Diogo M , Prieto Karla , Reyes Daniel , Bingham Andrea , Paul Lauren M , Robles-Sikisaka Refugio , Oliveira Glenn , Pronty Darryl , Metsky Hayden C , Baniecki Mary Lynn , Barnes Kayla G , Chak Bridget , Freije Catherine A , Gladden-Young Adrianne , Gnirke Andreas , Luo Cynthia , MacInnis Bronwyn , Matranga Christian B , Park Daniel J , Qu James , Schaffner Stephen F , Tomkins-Tinch Christopher , West Kendra L , Winnicki Sarah M , Wohl Shirlee , Yozwiak Nathan L , Quick Joshua , Fauver Joseph R , Khan Kamran , Brent Shannon E , Reiner Robert C , Lichtenberger Paola N , Ricciardi Michael , Bailey Varian K , Watkins David I , Cone Marshall R , Kopp Edgar W , Hogan Kelly N , Cannons Andrew C , Jean Reynald , Garry Robert F , Loman Nicholas J , Faria Nuno R , Porcelli Mario C , Vasquez Chalmers , Nagle Elyse R , Cummings Derek AT , Stanek Danielle , Rambaut Andrew , Sanchez-Lockhart Mariano , Sabeti Pardis C , Gillis Leah D , Michael Scott F , Bedford Trevor , Pybus Oliver G , Isern Sharon , Palacios Gustavo , Andersen Kristian G
Published: February 2017

Zika virus (ZIKV) is causing an unprecedented epidemic linked to severe congenital syndromes1,2. In July 2016, mosquito-borne ZIKV transmission was first reported in the continental United States and since then, hundreds of locally-acquired infections have been reported in Florida3. To gain insights into the timing, source, and likely route(s) of introduction of ZIKV into the continental United States, we tracked the virus from its first detection in Miami, Florida by direct sequencing of ZIKV genomes from infected patients andAedes aegyptimosquitoes. We show that at least four distinct ZIKV introductions contributed to the outbreak in Florida and that local transmission likely started in the spring of 2016 - several months before its initial detection. By analyzing surveillance and genetic data, we discovered that ZIKV moved among transmission zones in Miami. Our analyses show that most introductions are phylogenetically linked to the Caribbean, a finding corroborated by the high incidence rates and traffic volumes from the region into the Miami area. By comparing mosquito abundance and travel flows, we describe the areas of southern Florida that are especially vulnerable to ZIKV introductions. Our study provides a deeper understanding of how ZIKV initiates and sustains transmission in new regions.
Extensive Copy Number Variation in Fermentation-Related Genes amongSaccharomyces cerevisiaeWine Strains
Authors: Steenwyk Jacob , Rokas Antonis
Published: February 2017

Due to the importance ofSaccharomyces cerevisiaein wine-making, the genomic variation of wine yeast strains has been extensively studied. One of the major insights stemming from these studies is that wine yeast strains harbor low levels of genetic diversity in the form of single nucleotide polymorphisms (SNPs). Genomic structural variants, such as copy number (CN) variants, are another major type of variation segregating in natural populations. To test whether genetic diversity in CN variation is also low across wine yeast strains, we examined genome-wide levels of CN variation in 132 whole-genome sequences ofS. cerevisiaewine strains. We found an average of 97.8 CN variable regions (CNVRs) affecting ~4% of the genome per strain. Using two different measures of CN diversity, we found that gene families involved in fermentation-related processes such as copper resistance (CUP), flocculation (FLO), and glucose metabolism (HXT), as well as theSNOgene family whose members are expressed before or during the diauxic shift showed substantial CN diversity across the 132 strains examined. Importantly, these same gene families have been shown, through comparative transcriptomic and functional assays, to be associated with adaptation to the wine fermentation environment. Our results suggest that CN variation is a substantial contributor to the genomic diversity of wine yeast strains and identify several candidate loci whose levels of CN variation may affect the adaptation and performance of wine yeast strains during fermentation.
Predicting how and when hidden neurons skew measured synaptic interactions
Authors: Brinkman Braden A. W. , Rieke Fred , Shea-Brown Eric , Buice Michael A.
Published: February 2017

A major obstacle to understanding neural coding and computation is the fact that experimental recordings typically sample only a small fraction of the neurons in a circuit. Measured neural properties are skewed by interactions between recorded neurons and the “hidden” portion of the network. To properly interpret neural data and determine how biological structure gives rise to neural circuit function, we thus need a better understanding of the relationships between measured effective neural properties and the true underlying physiological properties. Here, we focus on how the effective spatiotemporal dynamics of the synaptic interactions between neurons are reshaped by coupling to unobserved neurons. We find that the effective interactions from a pre-synaptic neuronr′to a post-synaptic neuronrcan be decomposed into a sum of the true interaction fromr′torplus corrections from every directed path fromr′torthrough unobserved neurons. Importantly, the resulting formula reveals when the hidden units have—or do not have—major effects on reshaping the interactions among observed neurons. As a particular example of interest, we derive a formula for the impact of hidden units in random networks with “strong” coupling—connection weights that scale with, whereNis the network size, precisely the scaling observed in recent experiments. With this quantitative relationship between measured and true interactions, we can study how network properties shape effective interactions, which properties are relevant for neural computations, and how to manipulate effective interactions.
An Evaluation of Machine-learning for Predicting Phenotype: Studies in Yeast, Rice, and Wheat
Authors: Grinberg Nastasiya F. , Orhobor Oghenejokpeme I. , King Ross D.
Published: February 2017

In phenotype prediction, the physical characteristics of an organism are predicted from knowledge of its genotype and environment. Such studies are of the highest societal importance, as they are of central importance to medicine, crop-breeding, etc. We investigated three phenotype prediction problems: one simple and clean (yeast), and the other two complex and real-world (rice and wheat). We compared standard machine learning methods (elastic net, ridge regression, lasso regression, random forest, gradient boosting machines (GBM), and support vector machines (SVM)), with two state-of-the-art classical statistical genetics methods (including genomic BLUP). Additionally, using the clean yeast data, we investigated how performance varied with the complexity of the biological mechanism, the amount of observational noise, the number of examples, the amount of missing data, and the use of different data representations. We found that for almost all phenotypes considered standard machine learning methods outperformed the methods from classical statistical genetics. On the yeast problem, the most successful method was GBM, followed by lasso regression, and the two statistical genetics methods; with greater mechanistic complexity GBM was best, while in simpler cases lasso was superior. When applied to the wheat and rice studies the best two methods were SVM and BLUP. The most robust method in the presence of noise, missing data, etc. was random forests. The classical statistical genetics method of genomic BLUP was found to perform well on problems where there was population structure, which suggests one way to improve standard machine learning methods when population structure is present. We conclude that the application of machine learning methods to phenotype prediction problems holds great promise.
Assessment of the World Largest Afforestation Program: Success, Failure, and Future Directions
Authors: Zhu J. J. , Zheng X. , Wang G.G. , Wu B.F. , Liu S.R. , Yan C.Z. , Li Y. , Sun Y.R. , Yan Q.L. , Zeng Y. , Lu S.L. , Li X. F. , Song L.N. , Hu Z. B. , Yang K. , Yan N.N. , Li X.S. , Gao T. , Zhang J. X. , Ellison Aaron M.
Published: February 2017

The Three-North Afforestation Program (TNAP), initiated in 1978 and scheduled to be completed in 2050, is the world’s largest afforestation project and covers 4.07 x 106km2(42.4%) of China. We systematically assessed goals and outcomes of the first 30 years of the TNAP using high-resolution remote sensing and ground survey data. With almost 23 billion dollars invested between 1978 and 2008, the forested area within the TNAP region increased by 1.20 × 107ha, but the proportion of high quality forests declined by 15.8%. The establishment of shelterbelts improved crop yield by 1.7%, much lower than the 5.9% expected once all crop fields are fully protected by shelterbelts. The area subjected to soil erosion by water decreased by 36.0% from 6.72 × 107to 4.27 × 107ha; the largest reductions occurred in areas where soil erosion had been most severe and forests contributed more than half of this improvement. Desertification area increased from 1978 to 2000 but decreased from 2000 to 2008; the 30-year net reduction was 13.0% (4.05×106ha), with 8.0% being accounted for by afforestation in areas with only slight, prior desertification. In addition to its direct impacts, the TNAP has enhanced people’s awareness of environmental protection and attracted consistent attention and long-term commitment from the Chinese government to the restoration and protection of fragile ecosystems in the vast Three-North region. The significant decline in forest quality, limited success in reducing desertification, and low coverage of shelterbelts are aspects of the TNAP in need of re-assessment, and additional ca. 34 billion dollars will be needed to ensure the completion of the TNAP.
Free energy based high-resolution modeling of CTCF-mediated chromatin loops for human genome
Authors: Dawson Wayne , Plewczynski Dariusz
Published: February 2017

In recent years, chromatin has been found to have considerable structural organization in the human genome with diverse parts of the chromatin interacting with each other to form what have been termed topologically associated domains (TADs). Chromatin interaction analysis by paired-end tag sequencing (ChIA-PET) is a recent protein-specific method that measures these chromatin interactions via specific interactions such as CTCF-cohesin binding proteins or RNA polymerase II interactions. Unlike high-throughput chromosome conformation capture (Hi-C), which measures unspecific binding (all against all), ChIA-PET measures specific protein-protein contact interactions; hence physical bonds that reflect binding free energies. In this work, a thermodynamic method for computing the stability and dynamics of chromatin loops is proposed. The CTCF-mediated interactions, as observed in ChIA-PET experiments for human B-lymphoblastoid cells, are evaluated in terms of a chain folding polymer model and the experimentally observed frequency of contacts within the chromatin regions. To estimate the optimal free energy and a Boltzmann distribution of suboptimal structures, the approach uses dynamic programming with methods to handle degeneracy and heuristics to compute parallel and antiparallel chain stems and pseudoknots. Moreover, multiple loops mediated by CTCF protein binding that connects together more than one chain into multimeric islands are simulated using the model. Based on the thermodynamic properties of those topological three-dimensional structures, we predict the correlation between the relative activity of chromatin loop and the Boltzmann probability, or the minimum free energy, depending also on its genomic length. The results show that segments of chromatin where the structures show a more stable minimum free energy (for a given genomic distance) tend to be inactive, whereas structures that have lower stability in the minimum free energy (with the same genomic distance) tend to be active.
First indication of acetylcholine-based communication in honeybee haemocytes and its modulation by a neonicotinoid insecticide
Authors: Pamminger T. , Basley K. , Goulson D , Hughes WOH
Published: February 2017

There is growing concern that some managed and wild insect pollinator populations are in decline, potentially threatening biodiversity and sustainable food production on a global scale. In recent years, there has been increasing evidence that sub-lethal exposure to neurotoxic, neonicotinoid pesticides can negatively affect pollinator immunocompetence and amplify the effects of diseases, likely contributing to pollinator declines. Here we show that a range of non-neural tissues and haemocytes of the honeybeeApis melliferaexpress the nicotinic acetylcholine receptor that is the target of neonicotinoids. In addition, we demonstrate that the haemocytes, which form the cellular arm of the innate immune system, actively synthesize acetylcholine. This suggests the presence of a neural-independent acetylcholine-based immune signalling system in insects similar to that found in vertebrates. Lastly we establish that field-relevant doses of the neonicotinoid insecticide clothianidin alter this communication system. These findings provide a novel, mechanistically informed framework to understand the numerous siede-effects on insects of sub-lethal pesticide exposure, including immunosuppression. They support the growing evidence for acetylcholine-based immune regulation in invertebrates that operates independently of the nervous system.
Acetazolamide reduces exercise capacity following a five-day ascent to 4559 m on Monte Rosa
Authors: Bradwell Arthur R. , Ashdown Kimberly , Gallagher Carla , Delamere John , Thomas Owen D. , Lucas Samuel J.E. , Wright Alex D. , Harris Stephen J. , Myers Stephen D. ,   Birmingham Medical Research Expeditionary Society
Published: February 2017

Acetazolamide (Az) is widely used to prevent and treat the symptoms of acute mountain sickness (AMS) but whether it alters exercise capacity at high altitude is unclear. Az (250 mg twice daily) or placebo were administered to 20 healthy adults (age range, 21-77 years) in a double-blind, randomized manner. Participants ascended over five days to 4559 m, before undertaking an incremental exercise test to exhaustion on a bicycle ergometer, with breath-by-breath gas measurements recorded using a portable gas analysis system. Maximum power output (Pmax) was reduced on Az compared with placebo (p=0.03), as was maximum O2uptake (VO2max) (20.7 vs 24.6 mL/kg/min;p=0.06) and maximum expired CO2(VCO2max) (23.4 vs 29.5 mL/kg/min;p=0.01). Comparing individuals matched for similar characteristics, Az-treated participants had smaller changes than placebo-treated participants in minute ventilation (88 vs 116 L/min:p=0.05), end tidal O2(6.6 vs 9.3 mm Hg:p=0.009), end-tidal CO2(−2.3 vs −4.2 mm Hg:p=0.005), VO2max(9.8 vs 13.8 mL/kg/min;p=0.04) and VCO2max(14.7 vs 20.8 mL/kg/min;p=0.009). There was a negative correlation between the mean ages of paired vs placebo-treated individuals and differences in Pmaxreductions from base-line to altitude (r=−0.83:p<0.005) and HRmaxat altitude (r=−0.71;p=0.01). Glomerular filtration rate (measured at sea-level) declined with increasing age (r=−0.69;p=0.001). Thus, 250mg of Az twice daily reduced exercise performance, particularly in older individuals. The age-related effects of Az may reflect higher tissue concentrations due to reduced drug clearance in older people.
Millennia of genomic stability within the invasive Para C Lineage ofSalmonella enterica
Authors: Zhou Zhemin , Lundstrøm Inge , Tran-Dien Alicia , Duchêne Sebastián , Alikhan Nabil-Fareed , Sergeant Martin J. , Langridge Gemma , Fotakis Anna K. , Nair Satheesh , Stenøien Hans K. , Hamre Stian S. , Casjens Sherwood , Christophersen Axel , Quince Christopher , Thomson Nicholas R. , Weill François-Xavier , Ho Simon Y.W. , Gilbert M. Thomas P. , Achtman Mark
Published: February 2017

Salmonella entericaserovar Paratyphi C is the causative agent of enteric (paratyphoid) fever. While today a potentially lethal infection of humans that occurs in Africa and Asia, early 20thcentury observations in Eastern Europe suggest it may once have had a wider-ranging impact on human societies. We recovered a draft Paratyphi C genome from the 800-year-old skeleton of a young woman in Trondheim, Norway, who likely died of enteric fever. Analysis of this genome against a new, significantly expanded database of related modern genomes demonstrated that Paratyphi C is descended from the ancestors of swine pathogens, serovars Choleraesuis and Typhisuis, together forming the Para C Lineage. Our results indicate that Paratyphi C has been a pathogen of humans for at least 1,000 years, and may have evolved after zoonotic transfer from swine during the Neolithic period.

One Sentence Summary

The combination of an 800-year-oldSalmonella entericaParatyphi C genome with genomes from extant bacteria reshapes our understanding of this pathogen’s origins and evolution.
A recurrence based approach for validating structural variation using long-read sequencing technology
Authors: Zhao Xuefang , Weber Alexandra M. , Mills Ryan E.
Published: February 2017

Although there are numerous algorithms that have been developed to identify structural variation (SVs) in genomic sequences, there is a dearth of approaches that can be used to evaluate their results. The emergence of new sequencing technologies that generate longer sequence reads can, in theory, provide direct evidence for all types of SVs regardless of the length of region through which it spans. However, current efforts to use these data in this manner require the use of large computational resources to assemble these sequences as well as manual inspection of each region. Here, we present VaPoR, a highly efficient algorithm that autonomously validates large SV sets using long read sequencing data. We assess of the performance of VaPoR on both simulated and real SVs and report a high-fidelity rate for various features including overall accuracy, sensitivity of breakpoint precision, and predicted genotype.
Efficiency of genome-wide association study in random cross populations
Authors: Viana José Marcelo Soriano , Mundim Gabriel Borges , Pereira Hélcio Duarte , Andrade Andréa Carla Bastos , Silva Fabyano Fonseca e
Published: February 2017

Genome-wide association studies (GWAS) with plant species have employed inbred lines panels. Our objectives were to present additional quantitative genetics theory for GWAS, evaluate the relative efficiency of GWAS in non-inbred and inbred populations and in an inbred lines panel, and assess factors affecting GWAS. Fifty samples of 400 individuals from populations with linkage disequilibrium were simulated. Individuals were genotyped for 10,000 single nucleotide polymorphisms (SNPs) and phenotyped for traits controlled by 10 quantitative trait loci (QTLs) and 90 minor genes, assuming different degrees of dominance and heritabilities of 40 and 80%. The average SNP density was 0.1 centiMorgan and the QTL heritabilities ranged from 3.2 to 11.8%. To increase the QTL detection power, the additive-dominance model must be fitted for traits controlled by dominance effects but must not be fitted for traits showing no dominance. The power of detection was maximized increasing the sample size to 400 and the false discovery rate (FDR) to 5%. The average power of detection for the low, intermediate, and high heritability QTLs were 9.7, 32.7, and 87.7%, respectively. Under sample size of 400 the observed FDR was equal to or lower than the specified level of significance. The association mapping was highly precise. The analysis of the inbred random cross population provided essentially the same results from the non-inbred population. The inbred lines panel provided the best results concerning the low and intermediate heritability QTL detection power, FDR, and mapping precision. The FDR is mainly affected by population structure, compared to relationship information.
A population MRI brain template and analysis tools for the macaque
Authors: Seidlitz Jakob , Sponheim Caleb , Glen Daniel , Ye Frank Q. , Saleem Kadharbatcha S. , Leopold David A. , Ungerleider Leslie , Messinger Adam
Published: February 2017

The use of standard anatomical templates is common in human neuroimaging, as it facilitates data analysis and comparison across subjects and studies. For non-human primates, previousin vivotemplates have lacked sufficient contrast to reliably validate known anatomical brain regions and have not provided tools for automated single-subject processing. Here we present the “National Institute of Mental Health Macaque Template”, or NMT for short. The NMT is a high-resolutionin vivoMRI template of the average macaque brain generated from 31 subjects, as well as a neuroimaging tool for improved data analysis and visualization. From the NMT volume, we generated maps of tissue segmentation and cortical thickness. Surface reconstructions and transformations to previously published digital brain atlases are also provided. We further provide an analysis pipeline using the NMT that automates and standardizes the time-consuming processes of brain extraction, tissue segmentation, and morphometric feature estimation for anatomical scans of individual subjects. The NMT and associated tools thus provide a common platform for precise single-subject data analysis and for characterizations of neuroimaging results across subjects and studies.
Cocaine place conditioning strengthens location-specific hippocampal inputs to the nucleus accumbens
Authors: Sjulson Lucas , Peyrache Adrien , Cumpelik Andrea , Cassataro Daniela , Buzsáki György
Published: February 2017

Conditioned place preference (CPP) is a widely used model of addiction-related behavior whose underlying mechanism is not understood. In this study, we used dual site silicon probe recordings in freely moving mice to examine interactions between the hippocampus and nucleus accumbens in cocaine CPP. We found that CPP was associated with recruitment of nucleus accumbens medium spiny neurons to fire in the cocaine-paired location, and this recruitment was driven predominantly by selective strengthening of hippocampal inputs arising from place cells that encode the cocaine-paired location. These findings provide in vivo evidence that the synaptic potentiation in the accumbens caused by repeated cocaine administration preferentially affects inputs that were active at the time of drug exposure. This provides a potential physiological mechanism by which drug use becomes associated with specific environmental contexts.
Maximum entropy methods for extracting the learned features of deep neural networks
Authors: Finnegan Alex , Song Jun S.
Published: February 2017

New architectures of multilayer artificial neural networks and new methods for training them are rapidly revolutionizing the application of machine learning in diverse fields, including business, social science, physical sciences, and biology. Interpreting deep neural networks, however, currently remains elusive, and a critical challenge lies in understanding which meaningful features a network is actually learning. We present a general method for interpreting deep neural networks and extracting network-learned features from input data. We describe our algorithm in the context of biological sequence analysis. Our approach, based on ideas from statistical physics, samples from the maximum entropy distribution over possible sequences, anchored at an input sequence and subject to constraints implied by the empirical function learned by a network. Using our framework, we demonstrate that local transcription factor binding motifs can be identified from a network trained on ChIP-seq data and that nucleosome positioning signals are indeed learned by a network trained on chemical cleavage nucleosome maps. Imposing a further constraint on the maximum entropy distribution also allows us to probe whether a network is learning global sequence features, such as the high GC content in nucleosome-rich regions. This work thus provides valuable mathematical tools for interpreting and extracting learned features from feed-forward neural networks.
‘Tuning Out' or ‘Tuning in'? Mobile Music Listening and Intensified Encounters with the City
Authors: Watson Allan , Drakeford‐Allen Dominiqua
Published: February 2017

Mobile music listening has become an increasingly pervasive part of urban life. Yet it represents an area of enquiry with which urban studies scholars have yet to engage meaningfully. This essay considers the role of mobile music devices in creating new sonic, emotional and social interactions with and within the city. While academic work in this area has emphasized the use of these devices as a ‘tuning out' of the physicality of the city, we suggest that they might also be used as part of a ‘tuning in' that enhances the meaning and intensity of engagements with the city. In making this case, the essay considers two areas of academic enquiry that highlight the use of mobile music devices in intensified engagements with the city: first, recent writing on the sonic ecologies of the city that emphasize ‘city sounds' as part of the urban experience; and secondly, recent advances in the field of urban computing that provide technologies for location‐aware music exchanges and mediated social interactions. The essay emphasizes mobile music listening as one area of critical enquiry that can help develop our understanding of the ways in which the pervasiveness of mobile devices is recalibrating the experience of urban spatiality.
Identification and pharmacological characterization of succinate receptor agonists
Authors: Geubelle Pierre , Gilissen Julie , Dilly Sébastien , Poma Laurence , Dupuis Nadine , Laschet Céline , Abboud Dayana , Inoue Asuka , Jouret François , Pirotte Bernard , Hanson Julien
Published: February 2017

Background and Purpose

The succinate receptor (formerly GPR91 or SUCNR1) is described as a metabolic sensor that may be involved in homeostasis. Notwithstanding its implication in important (patho)physiological processes, the function of succinate receptors has remained ill‐defined because no pharmacological tools were available. We report on the discovery of the first family of potent synthetic agonists.

Experimental Approach

We screened a library of succinate analogues and analysed their activity on succinate receptors. Also, we modelled a pharmacophore and a binding site for this receptor. New agonists were identified based on the information provided by these two approaches. Their activity was studied in various bioassays, including measurement of cAMP levels, [Ca2+]i mobilization, TGF‐α shedding and recruitment of arrestin 3. The in vivo effects of activating succinate receptors with these new agonists was evaluated on rat BP.

Key Results

We identified cis‐epoxysuccinic acid and cis‐1,2‐cyclopropanedicarboxylic acid as agonists with an efficacy similar to that of succinic acid. Interestingly, cis‐epoxysuccinic acid was 10‐ to 20‐fold more potent than succinic acid on succinate receptors. For example, cis‐epoxysuccinic acid reduced cAMP levels with a pEC50 = 5.57 ± 0.02 (EC50 = 2.7 μM), compared with succinate pEC50 = 4.54 ± 0.08 (EC50 = 29 μM). The rank order of potency of the three agonists was the same in all in vitro assays. Both cis‐epoxysuccinic and cis‐1,2‐cyclopropanedicarboxylic acid were as potent as succinate in increasing rat BP.

Conclusions and Implications

We describe new agonists at succinate receptors that should facilitate further research on this understudied receptor.
NMR structure‐based optimization of Staphylococcus aureus sortase A pyridazinone inhibitors
Authors: Chan Albert H. , Yi Sung Wook , Weiner Ethan M. , Amer Brendan R. , Sue Christopher K. , Wereszczynski Jeff , Dillen Carly A. , Senese Silvia , Torres Jorge Z. , McCammon J. Andrew , Miller Lloyd S. , Jung Michael E. , Clubb Robert T.
Published: February 2017

Staphylococcus aureus is a leading cause of hospital‐acquired infections in the USA and is a major health concern as methicillin‐resistant S. aureus and other antibiotic‐resistant strains are common. Compounds that inhibit the S. aureus sortase (SrtA) cysteine transpeptidase may function as potent anti‐infective agents as this enzyme attaches virulence factors to the bacterial cell wall. While a variety of SrtA inhibitors have been discovered, the vast majority of these small molecules have not been optimized using structure‐based approaches. Here we have used NMR spectroscopy to determine the molecular basis through which pyridazinone‐based small molecules inhibit SrtA. These inhibitors covalently modify the active cysteine thiol and partially mimic the natural substrate of SrtA by inducing the closure of an active site loop. Computational and synthetic chemistry methods led to second‐generation analogues that are ~70‐fold more potent than the lead molecule. These optimized molecules exhibit broad‐spectrum activity against other types of class A sortases, have reduced cytotoxicity, and impair SrtA‐mediated protein display on S. aureus cell surface. Our work shows that pyridazinone analogues are attractive candidates for further development into anti‐infective agents, and highlights the utility of employing NMR spectroscopy and solubility‐optimized small molecules in structure‐based drug discovery.
Dynamic diversification history with rate upshifts in Holarctic bell‐flowers (Campanula and allies)
Authors: Jones Katy E. , Korotkova Nadja , Petersen Jörn , Henning Tilo , Borsch Thomas , Kilian Norbert
Published: February 2017

Campanula s.l. is one of the most speciose flowering plant lineages of the Holarctic (ca. 600 species). In the present study we sequenced three regions of the plastid genome (petD, rpl16 and trnK/matK) across a broad sample of Campanula s.l., which markedly improved phylogenetic resolution and statistical support compared to previous studies. Based on this robust phylogenetic hypothesis we estimated divergence times using BEAST, diversification rate shifts using Bayesian Analysis of Macroevolutionary Mixture (BAMM) and TreePar, and ancestral ranges using Biogeography with Bayesian (and likelihood) Evolutionary Analyses in R. Campanula s.l. is estimated to have originated during the Early Eocene but the major diversification events occurred between the Late Oligocene and Middle Miocene. Two upward diversification rate shifts were revealed by BAMM, specific to the crown nodes of two Campanula clades: CAM17, a mostly South European‐SW Asian lineage originating during the Middle Miocene and containing nearly half of all known Campanula species; and CAM15B, a SW Asian–Sino‐Himalayan lineage of nine species originating in the early Pleistocene. The dynamic diversification history of Campanula and the inferred rate shifts are discussed in a geo‐historical context.
Patient‐reported control of chronic rhinosinusitis symptoms is positively associated with general health‐related quality of life
Authors: Gray S.T. , Hoehle L.P. , Phillips K.M. , Caradonna D.S. , Sedaghat A.R.
Published: February 2017

Objective

In chronic rhinosinusitis (CRS), although patient‐reported severity of sinonasal symptoms is significantly associated with diminishment of patients’ general health‐related quality of life (QOL), it remains unclear whether patient‐perceived control of CRS symptomatology is associated with patients’ QOL. In this study, we sought to determine the association between patient‐perceived control of CRS symptomatology and QOL.

Design

Prospective cross‐sectional study.

Setting

Academic, tertiary care centre.

Participants

A cohort of 166 adults with CRS who were asked to categorise their level of CRS symptom control as “Not at all,” “A little,” “Somewhat,” “Very” and “Completely.”

Main outcome measure

General health‐related QOL, as reflected by the five‐dimensional EuroQol quality of life survey‐derived visual analogue scale (EQ5D‐VAS) and health utility values (EQ5D‐HUV).

Results

We found that higher EQ5D‐VAS scores were associated with CRS patients who classified their symptom control as “Very” (adjusted β=15.74, 95% CI: 5.44 to 26.04, P=.003) and “Completely” (adjusted β=14.24, 95% CI: 2.98 to 25.52, P=.014) compared to patients who classified their symptom control as “Not at all.” This was also true for higher EQ5D‐HUV which was associated with patient‐reported CRS symptom control of “A little” (adjusted β=0.10, 95% CI: 0.01 to 0.18, P=.024), “Somewhat” (adjusted β=0.08, 95% CI: 0.00 to 0.17, P=.049), “Very” (adjusted β=0.13, 95% CI: 0.05 to 0.21, P=.002) and “Completely” (adjusted β=0.18, 95% CI: 0.09 to 0.27, P<.001).

Conclusions

Higher levels of patient‐reported CRS symptom control are therefore associated with better QOL. These findings suggest that CRS symptom control should be targeted for improving patients’ QOL.
Management of the international development aid system: The Case of Tanzania
Authors: Furukawa Mitsuaki
Published: February 2017

This article tries to clarify Government behaviours as to how to manage aid in Tanzania. Contrary to the Organisation for Economic Co‐operation and Development (OECD) Development Assistance Committee (DAC) donor intentions, the development aid structure, carefully constructed under the poverty reduction regime in Tanzania, has led to Tanzanian‐owned initiatives toward a national development plan (NDP). Furthermore, this article shows that, in the process of creating an international development aid system, the Tanzanian Government has learned to manage aid in a recipient‐driven manner not only from DAC donors, but also from China.
Association Between Migraine and Atopic Diseases in Childhood: A Potential Protective Role of Anti‐Allergic Drugs
Authors: Aupiais Camille , Wanin Stephanie , Romanello Silvia , Spiri Daniele , Moretti Raffaella , Boizeau Priscilla , Massano Davide , Zuccotti Gian Vincenzo , Crichiutti Giovanni , Kanagarajah Lakshmi , Houdouin Veronique , Alberti Corinne , Titomanlio Luigi
Published: February 2017

Background

Migraine is a common cause of headache in childhood. Several studies have investigated the association between migraine and atopic diseases, mostly in the adult population.

Objective

This study aimed to investigate this association in children.

Methods

A case‐control study was conducted across 3 European tertiary care hospitals between June 2014 and August 2014. Cases (n = 229) were children aged 6‐18 years consulting for a migraine episode. Controls in the same age range (n = 406) were consulting for a minor injury and did not have a history of recurrent headache. Logistic regression analyses tested the effect of atopic diseases and anti‐allergic therapies on occurrence of migraine.

Results

Children with migraine were more likely to have persistent asthma compared to absence of asthma (odds ratio [OR]: 4.57, 95% confidence interval [CI]: 2.04‐10.24) and less likely to have been treated by inhaled or nasal corticosteroid (OR: 0.34, 95% CI: 0.15‐0.76) or antihistamine therapy (OR: 0.33, 95% CI: 0.18‐0.60). The median number of monthly migraine episodes was higher in children with persistent asthma (3; interquartile [IQR]: 1‐4; range: 0.5‐10) compared to children with intermittent asthma (2; IQR: 1‐3; range: 0.1‐4) or non‐asthmatic children (2; IQR: 1‐3; range: 0.1‐12) (P < .01).

Conclusion

Persistent childhood asthma was associated with increased risk of migraine and higher frequency of migraine attacks. History of anti‐asthmatic or anti‐allergic therapies was associated with decreased risk of migraine in children and adolescents. The role of these therapies on the pathogenesis and occurrence of migraine needs to be further elucidated because of the huge potential impact in terms of public health.
UNDERSTANDING THE LONG‐RUN DECLINE IN INTERSTATE MIGRATION
Authors: Kaplan Greg , Schulhofer‐Wohl Sam
Published: February 2017

We analyze the secular decline in gross interstate migration in the United States from 1991 to 2011. We argue that migration fell because of a decline in the geographic specificity of returns to occupations, together with an increase in workers' ability to learn about other locations before moving. Micro data on earnings and occupations across space provide evidence for lower geographic specificity. Other explanations do not fit the data. A calibrated model formalizes the geographic specificity and information mechanisms and is consistent with cross‐sectional and time‐series evidence. Our mechanisms can explain at least half of the decline in migration.
INNOVATION AND GROWTH WITH FINANCIAL, AND OTHER, FRICTIONS
Authors: Chiu Jonathan , Meh Cesaire , Wright Randall
Published: February 2017

The generation of ideas and their implementation are crucial for economic performance. We study this in a model of endogenous growth, where productivity increases with innovation and where the exchange of ideas (technology transfer) allows those with comparative advantage to implement them. Search, bargaining, and commitment frictions impede the idea market, however, reducing efficiency and growth. We characterize optimal policies involving subsidies to innovative and entrepreneurial activity, given both knowledge and search externalities. The role of liquidity is discussed. We show intermediation helps by financing more transactions with fewer assets and, more subtly, by ameliorating holdup problems. We also discuss some evidence.
PRODUCT FUNCTIONALITY, COMPETITION, AND MULTIPURCHASING
Authors: Anderson Simon P. , Foros Øystein , Kind Hans Jarle
Published: February 2017

The more functionalities a good offers, the greater is its perceived quality. Equilibrium prices in standard spatial competition models depend solely on quality differences. We assume that new functionalities are more appreciated the closer a product is to a consumer's ideal variety. Prices are then increasing in functionality levels. Furthermore, we endogenize whether consumers buy only one of two varieties (single‐purchase) or both (multipurchase). Under multipurchase, there might be a hump‐shaped relationship between equilibrium prices and functionality levels. Therefore, it could be optimal for each supplier to sacrifice sales and set prices so high that multipurchase is eliminated.
FERTILITY RISK IN THE LIFE CYCLE
Authors: Choi Sekyu
Published: February 2017

In this article, I study fertility decisions with special emphasis on the timing of births and abortions over the life cycle. Given the policy debate regarding abortion availability and recent evidence of its positive impact on women's outcomes, understanding the fertility process should help guide the discussion. Here, I present a life‐cycle model of consumption–savings and fertility decisions in an environment with uninsurable income shocks and imperfect fertility control. My model presents a framework in which both opportunity costs of child rearing and technological restrictions (in the form of contraception effectiveness) have roles shaping lifetime fertility choices.
Tb3Al2.5 Ga2.5O12 transparent ceramic for magneto‐optical application
Authors: Hao Deming , Feng Yue , Tang Yanru , Yi Xuezhuan , Zhang Shuai , Chen Chong , Lin Hui , Zhou Shengming
Published: February 2017

The optical quality and microstructure of the Tb3Al2.5 Ga2.5O12 transparent ceramic were investigated and compared with those of terbium gallium garnet (Tb3Ga5O12 TGG) and terbium aluminum garnet (Tb3Al5O12 TAG). The transmission of the Tb3Al2.5 Ga2.5O12 ceramic was as high as 80% in the visible and near‐infrared (IR) regions, which was close to the theoretical value. The Verdet constant of the Tb3Al2.5 Ga2.5O12 ceramic measured at 632.8 nm and room temperature was −150.6 rad/Tm, which was 12% larger than that of the TGG single crystal and 13% smaller than that of the TAG single crystal, and the Tb3Al2.5 Ga2.5O12 ceramic showed the highest transparency among these three samples.
Job satisfaction and resilience in psychiatric nurses: A study at the Institute of Mental Health, Singapore
Authors: Zheng Zhimin , Gangaram Poornima , Xie Huiting , Chua Stephanie , Ong Samantha Bee Cheng , Koh Sioh Eng
Published: February 2017

Job satisfaction ranks highly as one of the main factors influencing turnover rates among nurses. Mental health nursing has been reported to be a particularly stressful specialty, yet little is known about the level of job satisfaction among psychiatric nurses in Singapore. Resilience is defined as a means of adapting to stress at the workplace, and could serve as a factor influencing job satisfaction. The present study aimed to explore the current level of job satisfaction among psychiatric nurses working in the only tertiary psychiatric institution in Singapore, the influencing factors, and the relationship between resilience and job satisfaction. A survey questionnaire consisting of the following was administered to all eligible nurses working in the Institute of Mental Health between the period of 16–24 December 2014: (i) The McCloskey and Mueller Satisfaction Scale; (ii) The Resilience Scale; and (iii) sociodemographic data form. A total of 874 nurses were eligible for participation in the study, and a total of 748 nurses responded, totalling 85.6% response. A mean satisfaction score of 95.21 and mean resilience score of 125.74 were obtained. Mean satisfaction and resilience scores were the highest for nurses with longer working experience and those of older age. A positive and significant association between satisfaction and resilience scores (P = 0.001) was obtained. Psychiatric nurses in Singapore are generally satisfied with their job, but this can be further improved with the strengthening of personal resilience.