bluuebunny/crossref_metadata_2025 huggingface dataset:
Cognitive Enhancement in Schizophrenia
Authors: Gilleen James
Published: November 2017

Schizophrenia is characterized by a constellation of heterogeneous symptoms including hallucinations and delusions, motivational and social deficits, and cognitive impairments. Although positive symptoms have historically been the target for drug development, in recent years, attention has turned to cognitive and negative symptoms. Cognitive deficits in schizophrenia are associated with significant impairments in functional, social, and employment outcomes, and although they are widely researched and relatively well understood, there are no currently approved compounds to treat them. This chapter provides a selective review of the current status of approaches developed to improve cognition in schizophrenia. It covers pharmacological approaches as well as cognitive training and cognitive remediation techniques. It also explores the various study design issues and challenges that contribute to the difficulties in discovering reliable ways to improve the cognitive deficits present in schizophrenia.
Modeling Public Health and Healthcare Systems
Authors: Basu Sanjay
Published: November 2017

This book aims to empower readers to learn and apply engineering, operations research, and modeling techniques to improve public health programs and healthcare systems. Readers will engage in in-depth study of disease detection and control strategies from a “systems science” perspective, which involves the use of common engineering, operations research, and mathematical modeling techniques such as optimization, queuing theory, Markov and Kermack-McKendrick models, and microsimulation. Chapters focus on applying these techniques to classical public health dilemmas such as how to optimize screening programs, reduce waiting times for healthcare services, solve resource allocation problems, and compare macroscale disease control strategies that cannot be easily evaluated through standard public health methods such as randomized trials or cohort studies. The book is organized around solving real-world problems, typically derived from actual experiences by staff at nongovernmental organizations, departments of public health, and international health agencies. In addition to teaching the theory behind modeling methods, the book aims to confer practical skills to readers through practice in model implementation using the statistical software R.
Waiting Lines and Waiting Times
Authors: Basu Sanjay
Published: November 2017

This chapter seeks to determine if can we reduce the time it takes to deliver a public health or healthcare service, such as the long waiting times in emergency departments, long waiting lists for under-supported services such as drug rehabilitation, and vast periods of uncertainty for scarce commodities such as organ transplants. How can we minimize the time it takes to provide people with the services they need? Embedded in this question is the problem of making strategic decisions about distributing our resources. Should we invest in that new resource, or is our money better spent on something else? In this chapter, the reader will solve such problems using a common operations research method known as queuing systems, which are systems of equations that enable us to determine what factors influence the time that people wait in line.
Complexities of Epidemic Modeling
Authors: Basu Sanjay
Published: November 2017

The prior chapter derived and simulated the most basic epidemic model, assuming that people can be in only one of three states (susceptible, infected, or recovered) and that people mix homogeneously throughout the population. In this chapter, the author examines how the Kermack-McKendrick model can be extended to simulate a wide variety of complex diseases and circumstances and be adapted to incorporate the complex ways that people contact each other. Once we leave the context of the Kermack-McKendrick model, the calculation of R0 becomes complicated, so that the researcher must resort to simulation to identify what effect a disease will have in a population and to measure the potential impact of a public health intervention on the disease. The author additionally describes methods for simulating individual behavior in response to an epidemic.
Introduction
Authors: Franz Carleen , Ascherman Lee , Shaftel Julia
Published: November 2017

The introduction provides a case study illustrating the complexities of the interface between learning disabilities and psychiatric comorbidity. Educational challenges can exacerbate and muddy the presentation of psychiatric difficulties and lead to diagnostic disagreement and less than optimal treatment efforts. Clinicians may have limited exposure to learning disorders, relevant cognitive functioning, and appropriate assessments. When learning disabilities are accurately recognized and diagnosed, educational supports and interventions can play their roles in improving the long-term emotional outlook for a student and enhance future educational and vocational opportunities. The purpose of this book is to provide information about diagnosing learning disabilities as clearly as possible so that clinicians will gain confidence in advocating for appropriate cognitive and educational evaluations that will enhance the accuracy of their clinical conclusions.
Understanding the Legal Framework
Authors: Franz Carleen , Ascherman Lee , Shaftel Julia
Published: November 2017

This chapter describes the historical context of the legal basis of protections for students with disabilities by tracing civil rights and educational legislation of the last century. The Individuals With Disabilities Act of 2004 (IDEA) is described in detail, along with procedures and requirements for identifying students with Specific Learning Disabilities in school settings. The requirements for assessing, identifying, and qualifying public school students with learning disabilities are complex and time-consuming, which makes them difficult for families and nonschool personnel to comprehend. The Americans With Disabilities Act of 1990 and its 2008 Amendments Act are also described. A basic knowledge of relevant legal protections will assist the clinician to better support students and families.
Learning Disabilities in Reading
Authors: Franz Carleen , Ascherman Lee , Shaftel Julia
Published: November 2017

This chapter begins with a brief history of the controversy regarding teaching reading using the whole language versus phonics methods, including how these two teaching approaches affect students with reading disabilities. The development of reading skills is outlined, and the three interdependent components of reading as defined by the National Reading Panel are described (alphabetics, fluency, and comprehension). Various types of reading disabilities and their manifestations are illustrated with case studies. Emphasis is given to discussion of dyslexia and how it fits into an overall picture of reading disabilities. The chapter concludes with a description of the assessment process and intervention options for various types of reading difficulties.
Academic Assessment
Authors: Franz Carleen , Ascherman Lee , Shaftel Julia
Published: November 2017

Academic assessment is an essential component of comprehensive psychoeducational evaluation, and numerous assessment instruments are available to examine general academic achievement. Academic content includes reading, writing, mathematics, and oral language. This content can be measured at multiple levels from basic skills through advanced applications. For example, reading can be assessed from prerequisite oral phonemic skills through advanced comprehension. This chapter describes for clinicians two major tests: the Wechsler Individual Achievement Test III and the Woodcock-Johnson IV Tests of Achievement. Types of scores obtained from academic achievement testing and specifics of score interpretation are detailed. Interpretation must decipher the scores and perhaps disparate results to present a coherent picture of functioning.
Motor unit anatomy and physiology
Authors: Pitt Matthew
Published: November 2017

This chapter focuses on the signals recorded with needle electromyography (EMG) and the measurement of their specific parameters. These parameters include duration, amplitude, number of phases, and stability. The concept of the electrophysiologic biopsy and the explanation of unusual findings seen on EMG are introduced. In relation to the interference pattern, discussions of the firing rate, recruitment order, and interference pattern are given. Moving from the theoretical explanation of the findings, the problems of the accurate quantitative analysis of the motor unit potential are discussed and measures to improve quantification, particularly in children, are highlighted. The importance of filter settings, the storage of signals, and the different ways of collecting and analysing the potentials are all covered. This section finishes with discussion of the normative range for motor unit duration, and concludes with the automatic analysis of the interference pattern, including turns/amplitude analysis, number of short segments measurement, and envelope analysis.
Late Presentation for Care Among Patients With Chronic Hepatitis C: Prevalence and Risk Factors
Authors: Hansen Janne Fuglsang , Hallager Sofie , Øvrehus Anne , Weis Nina , Brehm Christensen Peer , Pedersen Court
Published: November 2017

Patients with chronic hepatitis C may have advanced fibrosis at first evaluation. Using the European Association for the Study of the Liver (EASL) definition (FibroScan® >9.5 kPa) for “late presenter for care” (LP), we found that 32% (169 of 527) of patients were LP. Being a LP was associated with increasing age and a history of alcohol overuse.
From pioneer to repressor: Bimodal foxd3 activity dynamically remodels neural crest regulatory landscapein vivo
Authors: Gavriouchkina Daria , Williams Ruth M , Lukoseviciute Martyna , Hochgreb-Hägele Tatiana , Senanayake Upeka , Chong-Morrison Vanessa , Thongjuea Supat , Repapi Emmanouela , Mead Adam , Sauka-Spengler Tatjana
Published: November 2017

The neural crest (NC) is a transient embryonic stem cell population characterised by its multipotency and broad developmental potential. Here, we perform NC-specific transcriptional and epigenomic profiling offoxd3-mutant versus wild type cellsin vivoto define the gene regulatory circuits controlling NC specification. Together with global binding analysis obtained by foxd3 biotin-ChIP and single cell profiles offoxd3-expressing premigratory NC, our analysis shows that during early steps of NC formation, foxd3 acts globally as a pioneer factor to prime the onset of genes regulating NC specification and migration by re-arranging the chromatin landscape, openingcis-regulatory elements and reshuffing nucleosomes. Strikingly, foxd3 then switches from an activator to its canonical role as a transcriptional repressor. Taken together, these results demonstrate that foxd3 acts bimodally in the neural crest as a switch from permissive to repressive nucleosome/chromatin organisation to maintain stemness and define cell fates.
The predictability of genomic changes underlying a recent host shift in Melissa blue butterflies
Authors: Chaturvedi Samridhi , Lucas Lauren K. , Nice Chris C. , Fordyce James A. , Forister Matthew L. , Gompert Zachariah
Published: November 2017

Despite accumulating evidence that evolution can be predictable, studies quantifying the predictability of evolution remain rare. Here, we measured the predictability of genome-wide evolutionary changes associated with a recent host shift in the Melissa blue butterfly (Lycaeides melissa). We asked whether and to what extent genome-wide patterns of evolutionary change in nature could be predicted (1) by comparisons among instances of repeated evolution, and (2) from SNP × performance associations in a lab experiment. We delineated the genetic loci (SNPs) most strongly associated with host use in twoL. melissalineages that colonized alfalfa. Whereas most SNPs were strongly associated with host use in none or one of these lineages, we detected a ~two-fold excess of SNPs associated with host use in both lineages. Similarly, we found that host-associated SNPs in nature could also be partially predicted from SNP × performance (survival and weight) associations in a lab rearing experiment. But the extent of overlap, and thus degree of predictability, was somewhat reduced. Although we were able to predict (to a modest extent) the SNPs most strongly associated with host use in nature (in terms of parallelism and from the experiment), we had little to no ability to predict the direction of evolutionary change during the colonization of alfalfa. Our results show that different aspects of evolution associated with recent adaptation can be more or less predictable, and highlight how stochastic and deterministic processes interact to drive patterns of genome-wide evolutionary change.
What can an evolutionary perspective on women’s health provide to the current public health paradigm? A case study on redefining thyroid cancer as a reproductive cancer
Authors: Fraser Abby
Published: November 2017

Incidence rates of non-communicable diseases in women are increasing worldwide and now contributing more to mortality and morbidity than reproductive health. Despite this universal trend, there is no recognition by the WHO of this phenomenon in women’s health. Additionally, thyroid cancer is considered a non-sex specific cancer despite female incidence rates being triple those of males. To understand why there are such conceptual limitations to women’s health, biomedicine - and its prevalence in western public health authorities - will be analysed from an anthropological perspective. In mind of these conceptual limitations, insights from evolutionary perspectives on health are introduced as well as how they may alleviate the conceptual barriers in the current biomedical paradigm. Using the example of breast cancer, the difference between a reproductive cancer in women, and cancer located in the reproductive tract will be explored. From this, the possibility that a cancer outside the reproductive tract can be directly influenced by reproductive function is explored in the specific case of thyroid cancer. Thyroid cancer and current public health approaches to preventing malignancies of the thyroid are examined to show the limitations of their scope. Furthermore, evidence supporting the direct link between thyroid function and reproductive function is presented. Current academic studies into the link between thyroid cancer and women’s reproductive function are analysed to show they are subject to the same conceptual limitations of women’s reproductive function as found previously in biomedicine. To conclude, I will introduce a new hypothesis for exploring the impact of women’s reproductive function on thyroid cancer incidence rates. This hypothesis will allow women’s health to be viewed holistically, and allows reproductive function to be investigated beyond parity. Thus, the conceptual limitations of women’s health in the public health paradigm will be alleviated.
Characterizing Cancer Drug Response and Biological Correlates: A Geometric Network Approach
Authors: Pouryahya Maryam , Oh Jung Hun , Mathews James , Deasy Joseph O. , Tannenbaum Allen
Published: November 2017

In the present work, we consider a geometric network approach to study common biological features of anticancer drug response. We use for this purpose the panel of 60 human cell lines (NCI-60) provided by the National Cancer Institute. Our study suggests that utilization of mathematical tools for network-based analysis can provide novel insights into drug response and cancer biology. We adopted a discrete notion of Ricci curvature to measure the robustness of biological networks constructed with a pre-treatment gene expression dataset and coupled the results with the GI50 response of the cell lines to the drugs. The link between network robustness and Ricci curvature was implemented using the theory of optimal mass transport. Our hypothesis behind this idea is that robustness in the biological network contributes to tumor drug resistance, thereby enabling us to predict the effectiveness and sensitivity of drugs in the cell lines. Based on the resulting drug response ranking, we assessed the impact of genes that are likely associated with individual drug response. For important genes identified, we performed a gene ontology enrichment analysis using a curated bioinformatics database which resulted in very plausible biological processes associated with drug response across cell lines and cell types from the biological and literature viewpoint. These results demonstrate the potential of using the mathematical network analysis in assessing drug response and in identifying relevant genomic biomarkers and biological processes for precision medicine.
Recovery of gene haplotypes from a metagenome
Authors: Nicholls Samuel M. , Aubrey Wayne , Edwards Arwyn , Grave Kurt de , Huws Sharon , Schietgat Leander , Soares André , Creevey Christopher J. , Clare Amanda
Published: November 2017

Elucidation of population-level diversity of microbiomes is a significant step towards a complete understanding of the evolutionary, ecological and functional importance of microbial communities. Characterizing this diversity requires the recovery of the exact DNA sequence (haplotype) of each gene isoform from every individual present in the community. To address this, we present Hansel and Gretel: a freely-available data structure and algorithm, providing a software package that reconstructs the most likely haplotypes from metagenomes. We demonstrate recovery of haplotypes from short-read Illumina data for a bovine rumen microbiome, and verify our predictions are 100% accurate with long-read PacBio CCS sequencing. We show that Gretel’s haplotypes can be analyzed to determine a significant difference in mutation rates between core and accessory gene families in an ovine rumen microbiome. All tools, documentation and data for evaluation are open source and available via our repository: https://github.com/samstudio8/gretel
Genomic insights into the domestication of the chocolate tree,Theobroma cacaoL
Authors: Cornejo Omar E. , Yee Muh-Ching , Dominguez Victor , Andrews Mary , Sockell Alexandra , Strandberg Erika , Livingstone Donald , Stack Conrad , Romero Alberto , Umaharan Pathmanathan , Royaert Stefan , Tawari Nilesh R. , Pauline Ng , Schnell Ray , Phillips Wilbert , Mockaitis Keithanne , Bustamante Carlos D. , Motamayor Juan C.
Published: November 2017

Domestication has had a strong impact on the development of modern societies. We sequenced 200 genomes of the chocolate plantTheobroma cacaoL. to show for the first time that a single population underwent strong domestication approximately 3,600 years (95% CI: 2481 – 10,903 years ago) ago, the Criollo population. We also show that during the process of domestication, there was strong selection for genes involved in the metabolism of the colored protectants anthocyanins and the stimulant theobromine, as well as disease resistance genes. Our analyses show that domesticated populations ofT. cacao(Criollo) maintain a higher proportion of high frequency deleterious mutations. We also show for the first time the negative consequences the increase accumulation of deleterious mutations during domestication on the fitness of individuals (significant negative correlation between Criollo ancestry and Kg of beans per hectare per year, P = 0.000425).
Epigenome-wide association in adipose tissue from the METSIM cohort
Authors: Orozco Luz D. , Farrell Colin , Hale Christopher , Rbi Liudmilla , Rinaldi Arturo , Civelek Mete , Pan Calvin , Lam Larry , Montoya Dennis , Edillor Chantle , Seldin Marcus , Mohlke Karen L , Jacobsen Steve , Kuusisto Johanna , Laakso Markku , Lusis Aldons J , Pellegrinil Matteo
Published: November 2017

Most epigenome-wide association studies to date have been conducted in blood. However, metabolic syndrome is mediated by a dysregulation of adiposity and therefore it is critical to study adipose tissue in order to understand the effects of this syndrome on epigenomes. To determine if natural variation in DNA methylation was associated with metabolic syndrome traits, we profiled global methylation levels in subcutaneous abdominal adipose tissue. We measured association between 32 clinical traits related to diabetes and obesity in 201 people from the Metabolic Syndrome In Men cohort. We performed epigenome-wide association studies between DNA methylation levels and traits, and identified associations for 13 clinical traits in 21 loci. We prioritized candidate genes in these loci using eQTL, and identified 18 high confidence candidate genes, including known and novel genes associated with diabetes and obesity traits. Using methylation deconvolution, we examined which cell types may be mediating the associations, and concluded that most of the loci we identified were specific to adipocytes. We determined whether the abundance of cell types varies with metabolic traits, and found that macrophages increased in abundance with the severity of metabolic syndrome traits. Finally, we developed a DNA methylation based biomarker to assess type II diabetes risk in adipose tissue. In conclusion, our results demonstrate that profiling DNA methylation in adipose tissue is a powerful tool for understanding the molecular effects of metabolic syndrome on adipose tissue, and can be used in conjunction with traditional genetic analyses to further characterize this disorder.
Genome-wide detection of genes under positive selection in worldwide populations of the barley scald pathogen
Authors: Mohd-Assaad Norfarhan , McDonald Bruce A. , Croll Daniel
Published: November 2017

The coevolution between hosts and pathogens generates strong selection pressures to maintain resistance and infectivity, respectively. Genomes of plant pathogens often encode major effect loci for the ability to successfully infect a specific host. Hence, heterogeneity in the host genotypes and abiotic factors leads to locally adapted pathogen populations. However, the genetic basis of local adaptation is poorly understood. We analyzed global field populations of Rhynchosporium commune, the pathogen causing barley scald disease, to identify candidate genes for local adaptation. Whole genome sequencing data generated for 125 isolates showed that the pathogen is subdivided into three genetic clusters associated with distinct geographic and climatic regions. Using haplotype-based selection scans applied independently to each genetic cluster, we found strong evidence for selective sweeps throughout the genome. Comparisons of loci under selection among clusters revealed little overlap, suggesting that ecological differences associated with each cluster led to variable selection regimes. The strongest signals of selection were found predominantly in the two clusters composed of isolates from Central Europe and Ethiopia. The strongest selective sweep regions encoded proteins with functions related to both biotic and abiotic stresses. We found that selective sweep regions were enriched in genes encoding functions in cellular localization, protein transport activity, and DNA damage responses. In contrast to the prevailing view that a small number of gene-for-gene interactions govern plant pathogen evolution, our analyses suggest that the evolutionary trajectory is largely determined by spatially heterogeneous biotic and abiotic selection pressures.
Developing a low-cost milliliter-scale chemostat array for precise control of cellular growth
Authors: Skelding David , Hart Sam , Vidyasagar Thejas , Pozhitkov Alexander E. , Shou Wenying
Published: November 2017

Multiplexed milliliter-scale chemostats are useful for measuring cell physiology under various degrees of nutrient limitation and for experimental evolution. In each chemostat, fresh medium containing a growth rate-limiting metabolite is pumped into the culturing chamber at a constant rate, while culture effluent exits at an equal rate. Although such devices have been developed by various labs, key parameters - the accuracy and precision of flow rate and the operational range - are not explicitly characterized. Here we report the development of multiplexed milliliter-scale chemostats where flow rates for eight chambers can be independently controlled to vary within a wide range, corresponding to population doubling times of 3~ 13 hours. Importantly, flow rates are precise and accurate without the use of expensive feedback systems. Among the eight chambers, the maximal coefficient of variation in flow rate is less than 3%, and average flow rates are only slightly below targets,i.e., 3-6% for 13-hour and 0.6-1.0% for 3-hour doubling times. This deficit is largely due to evaporation and should be correctable. We experimentally demonstrate that our device allows accurate and precise quantification of population phenotypes.
Architecture of human interphase chromosome determines the spatiotemporal dynamics of chromatin loci
Authors: Liu Lei , Shi Guang , Thirumalai D. , Hyeon Changbong
Published: November 2017

By incorporating the information of human chromosome inferred from Hi-C experiments into a heteropolymer model of chromatin chain, we generate a conformational ensemble to investigate its spatiotemporal dynamics. The heterogeneous loci interactions result in hierarchical organization of chromatin chain, which obeys compact space-filling (SF) statistics at intermediate length scale. Remarkably, the higher order architecture of the chromatin, characterized by the single universal Flory exponent (ν= 1/3) for condensed homopolymers, provides quantitative account of the dynamical properties of the chromosome. The local chromosome structures, exemplified by topologically associated domains (~ 0.1 − 1 Mb), display dynamics with fast relaxation time (≲ 50 sec), whereas the long-range spatial reorganization of the entire chromatinoccurs on a much longer time scale (≳ hour), suggestive of glass-like behavior. This key finding provides the dynamic basis of cell-to-cell variability. Active forces, modeled using stronger isotropic white noises, accelerate the relaxation dynamics of chromatin domain described by the low frequency modes. Surprisingly, they do not significantly change the local scale dynamics from those under passive condition. By linking the spatiotemporal dynamics of chromosome with its organization, our study highlights the importance of physical constraints in chromosome architecture on the sluggish dynamics.

Significance Statement

Chromosomes are giant chain molecules made of hundreds of megabase-long DNA intercalated with proteins. Structure and dynamics of interphase chromatin in space and time hold the key to understanding the cell type-dependent gene regulation. In this study, we establish that the crumpled and space-filling organization of chromatin fiber in the chromosome territory, characterized by a single universal exponent used to describe polymer sizes, is sufficient to explain the complex spatiotemporal hierarchy in chromatin dynamics as well as the subdiffusive motion of the chromatin loci. While seemingly a daunting problem at a first glance, our study shows that relatively simple principles, rooted in polymer physics, can be used to grasp the essence of dynamical properties of the interphase chromatin.
BCL11A interacts with SOX2 to control the expression of epigenetic regulators in lung squamous cell carcinoma
Authors: Lazarus Kyren A. , Hadi Fazal , Zambon Elisabetta , Bach Karsten , Santolla Maria-Francesca , Watson Julie K. , Correia Lucia L. , Das Madhumita , Ugur Rosemary , Pensa Sara , Becker Lukas , Campos Lia S. , Ladds Graham , Liu Pentao , Evan Gerard , McCaughan Frank , Le Quesne John , Lee Joo-Hyeon , Calado Dinis , Khaled Walid T.
Published: November 2017

Patients diagnosed with lung squamous cell carcinoma (LUSC) have limited targeted therapeutic options. We report here the identification and characterisation of the transcriptional regulator,BCL11A, as a LUSC oncogene. Analysis of cancer genomics datasets revealedBCL11Ato be upregulated in LUSC but not lung adenocarcinoma (LUAD). We demonstrated that knockdown ofBCL11Ain LUSC cell lines abolished xenograft tumour growth and its overexpressionin vivoled to lung airway hyperplasia and the development of reserve cell hyperplastic lesions. In addition, deletion ofBcl11ain the tracheal basal cells abolished the development of tracheosphere organoids while its overexpression led to solid tracheospheres with a squamous phenotype. At the molecular level we foundBCL11Ato be a target of SOX2 and we show that it is required for the oncogenic role of SOX2 in LUSC. Furthermore, we showed thatBCL11Aand SOX2 interact at the protein level and that together they co-regulated the expression of several transcription factors. We demonstrate that pharmacological inhibition of SETD8, a gene co-regulated by BCL11A and SOX2, alone or in combination with cisplatin treatment, shows significant selectivity to LUSC in comparison to LUAD cells. Collectively, these results indicate that the disruption of the BCL11A-SOX2 transcriptional program provides a future framework for the development of targeted therapeutic intervention for LUSC patients.
Evaluation of anti insulin receptor antibodies as potential novel therapies for human insulin receptoropathy
Authors: Brierley Gemma. V. , Siddle Kenneth. , Semple Robert. K.
Published: November 2017

Biallelic loss-of-function mutations in the insulin receptor (INSR) commonly cause extreme insulin resistance and early mortality. Therapeutic options are limited, but anti-INSR antibodies have previously been shown to activate two mutant receptors. This study evaluated four murine anti-INSR monoclonal antibodies, each capable of stimulating wildtype INSR signaling, against ten known pathogenic INSR mutants and one novel mutation, F248C. All the mutant INSR bound antibody. Eight mutants showed antibody-induced autophosphorylation while co-treatment with antibody and insulin increased maximal phosphorylation. After simultaneous knockdown of mouse Insr and expression of mutant INSR in 3T3-L1 adipocytes two antibodies activated signalingviaAKT preferentially over signaling via ERK1/2 for seven mutants. Two antibodies (83-7 and 83-14) stimulated glucose uptakeviaP193L, S323L, F382V, and D707A mutant INSR, with antibody response greater than insulin response for D707A. These findings suggest that selected monoclonal anti-INSR antibodies elicit sufficient signaling by some mutated INSR to be clinically significant.

One sentence summary

Anti-insulin receptor monoclonal antibodies can activate selected naturally occurring mutated human insulin receptors, raising the prospect of novel therapy for lethal recessive insulin resistance.
Magnetic resonance imaging for characterisation of a chick embryo model of cancer cell metastases
Authors: Herrmann Anne , Taylor Arthur , Murray Patricia , Poptani Harish , Sée Violaine
Published: November 2017

Background

Metastasis is the most common cause of death for cancer patients, hence its study has rapidly expanded over the past few years. To fully understand all the steps involved in metastatic dissemination,in vivomodels are required, of which murine ones are the most common. Therefore pre-clinical imaging methods have mainly been developed for small mammals. However, the potential of preclinical imaging techniques such as magnetic resonance imaging (MRI) to monitor cancer growth and metastasis in non-mammalianin vivomodels is not commonly used. We have here used MRI to measure primary neuroblastoma tumour size and presence of metastatic dissemination in a chick embryo model. We compared its sensitivity and accuracy to end-point fluorescence detection.

Methods

Human neuroblastoma cells were labelled with GFP and micron-sized iron particles (MPIOs) and implanted on the extraembryonic chorioallantoic membrane of the chick embryo at E7. T2 RARE, T2 weighted FLASH as well as time-of-flight MR angiography imaging was applied at E14. Primary tumours as well as metastatic deposits in the chick embryo were dissected post imaging to compare with MRI results.

Results

MPIO labelling of neuroblastoma cells allowedin ovoobservation of the primary tumour and tumour volume measurement non-invasively over time. Moreover, T2weighted and FLASH imaging permitted the detection of very small metastatic deposits in the chick embryo.

Conclusions

The use of contrast agents enabled the detection of metastatic deposits of neuroblastoma cells in a chick embryo model, thereby reinforcing the potential of this cost efficient and convenient, 3R compliant,in vivomodel for cancer research.
Nextstrain: real-time tracking of pathogen evolution
Authors: Hadfield James , Megill Colin , Bell Sidney M. , Huddleston John , Potter Barney , Callender Charlton , Sagulenko Pavel , Bedford Trevor , Neher Richard A.
Published: November 2017

Understanding the spread and evolution of pathogens is important for effective public health measures and surveillance. Nextstrain consists of a database of viral genomes, a bioinformatics pipeline for phylodynamics analysis, and an interactive visualisation platform. Together these present a real-time view into the evolution and spread of a range of viral pathogens of high public health importance. The visualization integrates sequence data with other data types such as geographic information, serology, or host species. Nextstrain compiles our current understanding into a single accessible location, publicly available for use by health professionals, epidemiologists, virologists and the public alike.

Availability and implementation

All code (predominantly JavaScript and Python) is freely available from github.com/nextstrain and the web-application is available at nextstrain.org.
Modelling the Dynamics of Biological Systems with the Geometric Hidden Markov Model
Authors: Vangelov Borislav , Barahona Mauricio
Published: November 2017

Many biological processes can be described geometrically in a simple way: stem cell differentiation can be represented as a branching tree and cell division can be depicted as a cycle. In this paper we introduce the geometric hidden Markov model (GHMM), a dynamical model whose goal is to capture the low-dimensional characteristics of biological processes from multivariate time series data. The framework integrates a graph-theoretical algorithm for dimensionality reduction with a latent variable model for sequential data. We analyzed time series data generated by an in silico model of a biomolecular circuit, the represillator. The trained model has a simple structure: the latent Markov chain corresponds to a two-dimensional lattice. We show that the short-term and long-term predictions of the GHMM reflect the oscillatory behaviour of the genetic circuit. Analysis of the inferred model with a community detection methods leads to a coarse-grained representation of the process.
Empirical test of crab-clam predator-prey model predictions: storm-driven phase shift to a low-density steady state
Authors: Glaspie Cassandra N. , Seitz Rochelle D. , Lipcius Romuald N.
Published: November 2017

A dynamic systems approach can predict steady states in predator-prey interactions, but there are very few empirical tests of predictions from predator-prey models. Here, we examine the empirical evidence for the low-density steady state predicted by a Lotka-Volterra model of a crab-clam predator-prey system using data from long-term monitoring, a field survey, and a field experiment. We show that Tropical Storm Agnes in 1972 likely resulted in a phase shift to a low-density state for the soft-shell clamMya arenaria, which was once a biomass dominant in Chesapeake Bay. This storm altered predator-prey dynamics betweenM. arenariaand the blue crabCallinectes sapidus, shifting from a system controlled from the bottom-up by prey resources, to a system controlled from the top-down by predation pressure on bivalves. Predator-prey models with these two species alone were capable of reproducing observations of clam densities and mortality rates, consistent with the idea thatC. sapidusare a major driver ofM. arenariapopulation dynamics. Over 40 y post-storm,M. arenariadensities hover near a low-density steady state predicted from the predator-prey model. Relatively simple models can predict phase shifts and identify alternative stable states, as shown by agreement between model predictions and field data in this system. The preponderance of multispecies interactions exhibiting nonlinear dynamics indicates that this may be a general phenomenon.
Cyclin-Dependent Kinase Activity is Required for Type I Interferon Production
Authors: Cingöz Oya , Goff Stephen P.
Published: November 2017

Recognition of nucleic acids results in the production of type I interferons (IFN), which activate the JAK/STAT pathway and promote the expression of IFN-stimulated genes (ISG). In a search for modulators of this pathway, we discovered a previously unknown requirement for cyclin-dependent kinases (CDK) in the production of type I IFN following nucleic acid sensing and virus infection. Inhibition of CDK activity or knockdown of CDK levels leads to a striking block in STAT activation and ISG expression. CDKs are not required for the initial nucleic acid sensing leading to IFN-β mRNA induction, nor for the response to exogenous IFN-α/β, but are critical for IFN-β release into culture supernatants, suggesting a post-transcriptional role for CDKs in type I IFN production. In the absence of CDK activity, we demonstrate a translational block specific for IFN-β, in which IFN-β mRNA is removed from the actively translating polysomes, while the distribution of other cellular mRNAs or global translation rates are unaffected. Our findings reveal a critical role for CDKs in the translation of IFN-β.
Crystal structure of 3,6,6-trimethyl-4-oxo-1-(pyridin-2-yl)-4,5,6,7-tetrahydro-1H-indazol-7-aminium chloride and its monohydrate
Authors: Mishnev Anatoly , Mengots Alvis , Turks Māris
Published: November 2017

The title compounds, C15H19N4O+·Cl−and C15H19N4O+·Cl−·H2O, obtained in attempts to synthesize metal complexes using tetrahydroindazole as a ligand, were characterized by NMR, IR and X-ray diffraction techniques. The partially saturated ring in the tetrahydroindazole core adopts a sofa conformation. An intramolecular N—H...N hydrogen bond formed by the protonated amino group and the N atom of the pyridyl substituent is found in the first structure. In the hydrochloride, the organic moieties are linked by two N—H...Cl−hydrogen bonds, forming aC(4) graph-set. In the hydrate crystal, a Cl−anion and a water molecule assemble the moieties into infinite bands showing hydrogen-bond patterns with graph setsC(6),R64(12) andR42(8). Organic moieties form π–π stacked supramolecular structures running along thebaxis in both structures.
rac-cis-5-Methyl-2,3-diphenyl-1,3-thiazolidin-4-one
Authors: Yennawar Hemant P. , Tierney John , Silverberg Lee J.
Published: November 2017

In the racemic title compound, C16H15NOS, the thiazolidine ring adopts an envelope conformation, with the S atom as the flap. The dihedral angles between the heterocycle (all atoms) and pendant C– and N-bound benzene rings are 69.75 (14) and 56.56 (11)°, respectively; the aromatic rings are almost orthogonal to each other, with a dihedral angle of 76.04 (14)° between them. In the crystal, molecules are linked by weak C—H...O hydrogen bonds to generate [101] chains, with alternating molecules being enantiomers. A weak C—H...π interaction is also observed.
(E)-4-Fluoro-2-[(phenylimino)methyl]phenol
Authors: Swetha G. , Ida Malarselvi R. , Ramachandra Raja C. , Thiruvalluvar A. , Priscilla J.
Published: November 2017

The title compound, C13H10FNO, is essentially planar (r.m.s. deviation = 0.022 Å) and the dihedral angle between the planes of the two aryl rings is 0.69 (15)°. An intramolecular O—H...N hydrogen bond generates anS(6) ring. The crystal structure features C—H...O hydrogen bonds.
Flight test of fault-tolerant flight control system using simple adaptive control with PID controller
Authors: Matsuki Hidenobu , Nishiyama Taishi , Omori Yuya , Suzuki Shinji , Masui Kazuya , Sato Masayuki
Published: November 2017

Purpose

This paper aims to demonstrate the effectiveness of a fault-tolerant flight control method by using simple adaptive control (SAC) with PID controller.

Design/methodology/approach

Numerical simulations and flight tests are executed for pitch angle and roll angle control of research aircraft MuPAL-α under the following fault cases: sudden reduction in aileron effectiveness, sudden reduction in elevator effectiveness and loss of longitudinal static stability.

Findings

The simulations and flight tests reveal the effectiveness of the proposed SAC with PID controller as a fault-tolerant flight controller.

Practical implications

This research includes implications for the development of vehicles’ robustness.

Originality/value

This study proposes novel SAC-based flight controller and actually demonstrates the effectiveness by flight test.
Large eddy simulation of airfoil self-noise using OpenFOAM
Authors: Kamliya Jawahar Hasan , Lin Yujing , Savill Mark
Published: November 2017

Purpose

The purpose of this paper is to investigate airfoil self-noise generation and propagation by using a hybrid method based on the large-eddy simulation (LES) approach and Curle’s acoustic analogy as implemented in OpenFOAM.

Design/methodology/approach

Large-eddy simulation of near-field flow over a NACA6512-63 airfoil at zero angle of attack with a boundary layer trip at Rec = 1.9 × 105 has been carried out using the OpenFOAM® computational fluid dynamics (CFD) code. Calculated flow results are compared with published experimental data. The LES includes the wind tunnel installation effects by using appropriate inflow boundary conditions obtained from a RANS κ – ω SST model computation of the whole wind tunnel domain. Far-field noise prediction was achieved by an integral method based on Curle’s acoustic analogy. The predicted sound pressure levels are validated against the experimental data at various frequency ranges.

Findings

The numerical results presented in this paper show that the flow features around a NACA6512-63 airfoil have been correctly captured in OpenFOAM LES calculations. The mean surface pressure distributions and the local pressure peaks for the step trip setup agree very well with the experimental measurements. Aeroacoustic prediction using Curle’s analogy shows an overall agreement with the experimental data. The sound pressure level-frequency spectral analysis produces very similar data at low to medium frequency, whereas the experimentally observed levels are slightly over predicted at a higher frequency range.

Practical implications

This study has achieved and evaluated an alternative aeroacoustic simulation method based on the combination of LES with a simple Smagorinsky SGS model and Curle’s analogy, as implemented in the OpenFOAM CFD code. The unsteady velocity/pressure source data produced can be used for any simpler analytically based far-field noise prediction scheme.

Originality/value

A complete integration of the LES and Curle’s acoustic analogy for aeroacoustic simulations has been achieved in OpenFOAM. The capability and accuracy of the hybrid method are fully evaluated for high-camber airfoil self-noise predictions. Wind tunnel installation effects have been incorporated properly into the LES.
An assessment of flight efficiency based on the point merge system at metroplex airports
Authors: Sahin Ozlem , Usanmaz Oznur , Turgut Enis T.
Published: November 2017

Purpose

Metroplex is a system of two or more airports, in physical proximity, with highly interdependent arrival and departure operations. The purpose of this study is the construction of an efficient and effective air route model based on the point merge system (PMS) to reduce aircraft fuel consumption and CO2 emissions for three metroplex airports in Istanbul terminal control area (TMA).

Design/methodology/approach

A PMS arrival route model is constructed for metroplex airports. In the proposed model, two situations are taken into consideration: for delay which can be defined as flying on sequencing legs (PMSdel) and for no delay (PMSno del). An empirical model is developed using a data set including the flight data records of ten actual B737-800 domestic flights. With this empirical model, both the baseline and the PMS models (PMSdel and PMSno del) are compared in terms of fuel consumption, CO2 emissions and flight distance and time as a theoretical computation.

Findings

In the proposed PMSno del arrival route model, according to different entry points for Istanbul Ataturk International Airport (LTBA), the analyses show an average reduction of 26 per cent in flight time, 24.5 per cent in flight distance, 17 per cent in fuel burned and CO2 emissions; in addition, for Sabiha Gökcen International Airport (LTFJ) there are 34, 23 and 32 per cent average savings for flight time, flight distance and fuel burned together with CO2 emissions obtained, respectively. Even if the PMSdel model, for LTFJ except only one entry point, for LTBA except two entry points, better results are obtained than baseline.

Practical implications

The point merge model for metroplex airports in this paper can be applied by airspace designers and Air Navigation Service Providers to perform efficient and effective arrival routes.

Originality/value

In this study, a point merge model is constructed for metroplex airports. Quantitative results, using an empirical model, are achieved in terms of fuel consumption, CO2 emissions and flight distance and time at metroplex airports.
Adaptive robust control of coupled attitude and orbit for spacecraft with model uncertainties
Authors: Sun Jun , Wu Xiande , Zhang Shijie , Guo Fengzhi , Song Ting
Published: November 2017

Purpose

The purpose of this paper is to propose an adaptive robust controller for coupled attitude and orbit control of rigid spacecraft based on dual quaternion in the presence of external disturbances and model uncertainties.

Design/methodology/approach

First, based on dual quaternion, a theoretical model of the relative motion for rigid spacecraft is introduced. Then, an adaptive robust controller which can realize coordinated control of attitude and orbit is designed in the existence of external disturbances and model uncertainties.

Findings

This paper takes advantage of the Lyapunov function which can guarantee the asymptotic stabilization of the whole system in the existence of parameters uncertainties. Simulation results show that the proposed controller is feasible and effective.

Originality/value

This paper proposes a coupled attitude and orbit adaptive robust controller based on dual quaternion. Simulation results demonstrate that the proposed controller can achieve higher control performance in the presence of parameters uncertainties.