bluuebunny/crossref_metadata_2025 huggingface dataset:
Prioritizing putatively etiological T cell epitopes across autoimmune diseases
Authors: Ogishi Masato
Published: March 2019

Autoimmune diseases remain a leading cause of mortality among adolescents and young adults worldwide. Despite their clinical impact, there are still significant knowledge gaps in our understanding of immunological tolerance and its breach that characterizes the onset of autoimmune diseases. Genetic associations between the histocompatibility leukocyte antigen (HLA) loci and various autoimmune diseases have been well established. The HLA class I and class II molecules present epitopes to T cells, and T cells play indispensable roles both in the maintenance of tolerance and the pathogenesis of autoimmune diseases. Although a vast number of epitopes and reactive T cell clones have been identified from animal model studies and observational studies, however, only a few have been proven to be causally relevant to disease pathogenesis. Here, we propose a computational framework to prioritize etiologically relevant epitopes by integrating the putatively causal associations between HLA alleles and disease risk identified from population genetics; we define a metric, termed “differential presentation index (DPI),” which principally reflects the relative difference of epitope abundance presented onto HLA molecules whose alleles are genetically predisposing to or protective against the specific disease. We systematically examined publicly available epitope sequence data previously studied in the context of autoimmune diseases. Self-epitopes were generally more stably presented on disease-protective HLAs than non-self epitopes, and hence had a negative DPI. Conversely, proteome-wide sequence alignment revealed that epitopes with highly positive DPI were less similar to self. As a case study, we performed a focused analysis of multiple sclerosis (MS), and identified epitopes from myelin basic protein (MBP), a well-established MS autoantigen, based on DPI-guided prioritization. Moreover, we found several non-MBP-derived self-epitopes with high DPI that are potentially involved in the pathogenesis of MS. Our framework facilitates the identification of etiologically relevant epitopes across autoimmune diseases with known HLA allele association, which in turn expedites the development of epitope-specific disease monitoring and intervention strategies.
Active behaviour during early development shapes glucocorticoid reactivity
Authors: Castillo-Ramírez Luis A. , Ryu Soojin , De Marco Rodrigo J.
Published: March 2019

Glucocorticoids are the final effectors of the stress axis, with numerous targets in the central nervous system and the periphery. They are essential for adaptation, yet currently it is unclear how early life events program the glucocorticoid response to stress. Here we provide evidence that involuntary swimming at early developmental stages can reconfigure the cortisol response to homotypic and heterotypic stress in larval zebrafish (Danio rerio), also reducing startle reactivity and increasing spontaneous activity as well as energy efficiency during active behaviour. Collectively, these data identify a role of the genetically malleable zebrafish for linking early life stress with glucocorticoid function in later life.
The human proteome co-regulation map reveals functional relationships between proteins
Authors: Kustatscher Georg , Grabowski Piotr , Schrader Tina A. , Passmore Josiah B. , Schrader Michael , Rappsilber Juri
Published: March 2019

The annotation of protein function is a longstanding challenge of cell biology that suffers from the sheer magnitude of the task. Here we present ProteomeHD, which documents the response of 10,323 human proteins to 294 biological perturbations, measured by isotope-labelling mass spectrometry. Using this data matrix and robust machine learning we create a co-regulation map of the cell that reflects functional associations between human proteins. The map identifies a functional context for many uncharacterized proteins, including microproteins that are difficult to study with traditional methods. Co-regulation also captures relationships between proteins which do not physically interact or co-localize. For example, co-regulation of the peroxisomal membrane protein PEX11β with mitochondrial respiration factors led us to discover a novel organelle interface between peroxisomes and mitochondria in mammalian cells. The co-regulation map can be explored atwww.proteomeHD.net.
Cell morphology and nucleoid dynamics in dividing D. radiodurans
Authors: Floc’h Kevin , Lacroix Françoise , Servant Pascale , Wong Yung-Sing , Kleman Jean-Philippe , Bourgeois Dominique , Timmins Joanna
Published: March 2019

Our knowledge of bacterial nucleoids originates mostly from studies of rod- or crescent-shaped bacteria. Here, we reveal that Deinococcus radiodurans, a relatively large, spherical bacterium, possessing a multipartite genome, and well-known for its radioresistance, constitutes a valuable system for the study of nucleoids in cocci. Using advanced microscopy, we show that as D. radiodurans progresses through its cell cycle, it undergoes coordinated morphological changes at both the cellular and nucleoid level. D. radiodurans nucleoids were found to be highly condensed, but also surprisingly dynamic, adopting multiple distinct configurations and presenting a novel chromosomal arrangement in which oriC loci are radially distributed around clustered ter sites maintained at the centre of cells. Single-molecule and ensemble studies of the abundant histone-like HU protein suggest that its loose binding to DNA may contribute to this remarkable plasticity. These findings clearly demonstrate that nucleoid organization is complex and tightly coupled to cell cycle progression.
Analysis-ready datasets for insecticide resistance phenotype and genotype frequency in African malaria vectors
Authors: Moyes Catherine L. , Wiebe Antoinette , Gleave Katherine , Trett Anna , Hancock Penelope A. , Padonou Germain Gil , Chouaïbou Mouhamadou S. , Sovi Arthur , Abuelmaali Sara A. , Ochomo Eric , Antonio-Nkondjio Christophe , Dengela Dereje , Kawada Hitoshi , Dabire Roch K. , Donnelly Martin J. , Mbogo Charles , Fornadel Christen , Coleman Michael
Published: March 2019

The impact of insecticide resistance in malaria vectors is poorly understood and quantified. Here a series of geospatial datasets for insecticide resistance in malaria vectors are provided so that trends in resistance in time and space can be quantified and the impact of resistance found in wild populations on malaria transmission in Africa can be assessed. Data are also provided for common genetic markers of resistance to support analyses of whether these genetic data can improve the ability to monitor resistance in low resource settings. Specifically, data have been collated and geopositioned for the prevalence of insecticide resistance, as measured by standard bioassays, in representative samples of individual species or species complexes. Data are provided for theAnopheles gambiaespecies complex, theAnopheles funestussubgroup, and for nine individual vector species. In addition, allele frequencies for known resistance associated markers in the Voltage-gated sodium channel (Vgsc) are provided. In total, eight analysis-ready, standardised, geopositioned datasets encompassing over 20,000 African mosquito collections between 1957 and 2017 are provided.
Strain- or Stress-sensing in mechanochemical patterning by the phytohormone auxin
Authors: Julien Jean-Daniel , Pumir Alain , Boudaoud Arezki
Published: March 2019

Both chemical and mechanical fields are known to play a major role in morphogenesis. In plants, the phytohormone auxin and its directional transport are essential for the formation of robust patterns of organs, such as flowers or leaves, known as phyllotactic patterns. The transport of auxin was recently shown to be affected by mechanical signals, and conversely, auxin accumulation in incipient organs affects the mechanical properties of the cells. The precise interaction between mechanical fields and auxin transport, however, is poorly understood. In particular, it is unknown whether transport is sensitive to the strain or to the stress exerted on a given cell. Here, we investigate the nature of this coupling with the help of theoretical models. Namely, we introduce the effects of either mechanical stress or mechanical strain in a model of auxin transport, and compare the patterns predicted with available experimental results, in which the tissue is perturbed by ablations, chemical treatments, or genetic manipulations. We also study the robustness of the patterning mechanism to noise and investigate the effect of a shock that changes abruptly its parameters. Although the model predictions with the two different feedbacks are often indistinguishable, the strain-feedback seems to better agree with some of the experiments. The computational modeling approach used here, which enables us to distinguish between several possible mechanical feedbacks, offers promising perspectives to elucidate the role of mechanics in tissue development, and may help providing insight into the underlying molecular mechanisms.
Familial influences on Neuroticism and Education in the UK Biobank
Authors: Cheesman R. , Coleman J. , Rayner C. , Purves K.L. , Morneau-Vaillancourt G. , Glanville K. , Choi S.W. , Breen G. , Eley T.C.
Published: March 2019

Genome-wide studies often exclude family members, even though they are a valuable source of information. We identified parent-offspring pairs, siblings and couples in the UK Biobank and implemented a family-based DNA-derived heritability method to capture additional genetic effects and multiple sources of environmental influence on neuroticism and years of education. Compared to estimates from unrelated individuals, heritability increased from 10% to 27% and from 19% to 57% for neuroticism and education respectively by including family-based genetic effects. We detected no family environmental influences on neuroticism, but years of education was substantially influenced by couple similarity (38%). Overall, our genetic and environmental estimates closely replicate previous findings from an independent sample, but more research is required to dissect contributions to the additional heritability, particularly rare and structural genetic effects and residual environmental confounding. The latter is especially relevant for years of education, a highly socially-contingent variable, for which our heritability estimate is at the upper end of twin estimates in the literature. Family-based genetic effects narrow the gap between twin and DNA-based heritability methods, and could be harnessed to improve polygenic prediction.
MM-MRE: a new technique to quantify individual muscle forces during isometric tasks of the wrist using MR elastography
Authors: Zonnino Andrea , Smith Daniel R. , Delgorio Peyton L. , Johnson Curtis L. , Sergi Fabrizio
Published: March 2019

Non-invasive in-vivo measurement of individual muscle force is limited by the infeasibility of placing force sensing elements in series with the musculo-tendon structures. At the same time, estimating muscle forces using EMG measurements is prone to inaccuracies, as EMG is not always measurable for the complete set of muscles acting around the joints of interest. While new methods based on shear wave elastography have been recently proposed to directly characterize muscle mechanics, they can only be used to measure muscle forces in a limited set of superficial muscles. As such, they are not suitable to study the neuromuscular control of movements that require coordinated action of multiple muscles.

In this work, we present multi-muscle magnetic resonance elastography (MM-MRE), a new technique capable of quantifying individual muscle force from the complete set of muscles in the forearm, thus enabling the study of the neuromuscular control of wrist movements. MM-MRE integrates measurements of joint torque provided by an MRI-compatible instrumented handle with muscle-specific measurements of shear wave speed obtained via MRE to quantify individual muscle force using model-based estimator.

A single-subject pilot experiment demonstrates the possibility of obtaining measurements from individual muscles and establishes that MM-MRE has sufficient sensitivity to detect changes in muscle mechanics following the application of isometric joint torque with self-selected intensity.
Epistatic Transcription Factor Networks Differentially Modulate Arabidopsis Growth and Defense
Authors: Li Baohua , Tang Michelle , Caseys Céline , Nelson Ayla , Zhou Marium , Zhou Xue , Brady Siobhan M. , Kliebenstein Daniel J.
Published: March 2019

Plants integrate internal and external signals to finely coordinate growth and defense allowing for maximal fitness within a complex environment. One common model for the relationship between growth and defense is a trade-off model in which there is a simple negative interaction between growth and defense theoretically driven by energy costs. However, there is a developing consensus that the coordination of growth and defense likely involves a more conditional and intricate connection. To explore how a transcription factor network may coordinate growth and defense, we used high-throughput phenotyping to measure growth and flowering in a set of single and pairwise mutants previously linked to the aliphatic glucosinolate defense pathway. Showing the link between growth and aliphatic glucosinolate defense, 17 of the 20 tested TFs significantly influence plant growth and/or flowering time. These effects were conditional upon the environment, age of the plant and more critically varied amongst the phenotypes when using the same genotype. The phenotypic effects of the TF mutants on SC GLS accumulation and on growth did not display a simple correlation, supporting the coordination model. We propose that large transcription factor networks create a system to integrate internal and external signals and separately modulate growth and the accumulation of the defensive aliphatic GLS.
MitoToxy Assay: a novel cell-based method for the assessment of metabolic toxicity in a multiwell plate format using a lactate FRET nanosensor, Laconic
Authors: Contreras-Baeza Y , Ceballo S , Arce-Molina R , Sandoval PY , Alegría K , Barros L.F. , San Martín A.
Published: March 2019

Mitochondrial toxicity is a primary source of pre-clinical drug attrition. Methods that detect mitochondrial toxicity as early as possible during the drug development process are required. Here we introduce a new method for detecting mitochondrial toxicity based on MDA-MB-231 cells stably expressing the genetically-encoded FRET lactate indicator, Laconic. The method takes advantage of the high cytosolic lactate accumulation observed during mitochondrial stress, regardless of the specific toxicity mechanism, explained by compensatory glycolytic activation. IC50 determination using a standard multi-well plate reader, shown that the methodology allowed to detect metabolic toxicity induced by azide, antimycin, oligomycin, rotenone and myxothiazol with high sensitivity. Suitability for high-throughput screening applications was evaluated resulting in a Z’-factor > 0.5 and CV% < 20. A pilot screening allowed sensitive detection of commercial drugs that were previously withdrawn from the market due to liver/cardiac toxicity issues, such as camptothecin, ciglitazone, troglitazone, rosiglitazone, and terfenadine, in ten minutes. We envisage that the availability of this technology, based on a fluorescent genetically-encoded indicator will allow direct assessment of mitochondrial metabolism, and will make the early detection of mitochondrial toxicity in the drug development process possible, saving time and resources.
Using cell yields and qPCR to estimate biotic contribution to 1,1,1-trichloroethane dechlorination at a field site treated with granular zero valent iron and guar gum
Authors: Yang M. Ivy , Previdsa Michael , Edwards Elizabeth A. , Sleep Brent E.
Published: March 2019

Chlorinated ethanes are environmental pollutants found frequently at many contaminated industrial sites. 1,1,1-Trichloroethane (1,1,1-TCA) can be dechlorinated and detoxified via abiotic transformation or biologically by the action of dechlorinating microorganisms such asDehalobacter(Dhb). At a field site, it is challenging to distinguish abiotic vs biotic mechanisms as both processes share common transformation products. In this study, we evaluated using theDhb16S rRNA gene and specific reductive dehalogenase genes as biomarkers for 1,1,1-TCA and 1,1-dichloroethane (1,1-DCA) dechlorination. We analyzed samples from laboratory groundwater microcosms and from an industrial site where a mixture of granular zero valent iron (ZVI) and guar gum was injected for 1,1,1-TCA remediation. Abiotic and biotic transformation products were monitored and the changes in dechlorinating organisms were tracked using quantitative PCR (qPCR) with primers targeting theDhb16S rRNA gene and two functional genescfrAanddcrAencoding enzymes that dechlorinate 1,1,1-TCA to 1,1-DCA and 1,1-DCA to chloroethane (CA), respectively. The abundance of thecfrA- anddcrA-like genes confirmed that the two dechlorination steps were carried out by two distinctDhbpopulations at the site. Using cell yields established in laboratory microcosms along with measured abundances of theDhb16S rRNA gene in site samples, biotic and abiotic transformation of 1,1,1-TCA at the site was estimated. The biomarkers used in this study proved useful for tracking biodechlorination of 1,1,1-TCA and 1,1-DCA where both abiotic (e.g. with ZVI) and biotic processes co-occur.
A transcription factor Abf1 facilitates ORC binding onto theSaccharomyces cerevisiaereplication origin via histone acetylase Gcn5
Authors: Kohzaki Hidetsugu , Murakami Yota
Published: March 2019

Chromatin structure has been implicated in the regulation of DNA replication but the molecular mechanism involved is unclear. In this study, we observed that binding of the transcription factor Abf1 to the replication originARS1facilitated the association of the origin recognition complex (ORC) withARS1using genetic interaction analysis and ChIP assay. The histone acetyltransferases (HATs), Gcn5 and Esa1, were also loaded ontoARS1in an Abf1 site-dependent manner, where they were then responsible for acetylating histone H3 lysine 18 (H3K18) and histone H4 lysine 12 (H4K12), respectively. Interestingly, Abf1 interacted with Gcn5, while ORC interacted with Esa1. Indeed the B3 element showed genetic interaction with Gcn5 and Rpd3 not with Esa1, Act3 and Tra1.

These data suggest that Gcn5, which is recruited by Abf1, alters chromatin structure via histone acetylation and facilitates the loading of ORC. We therefore propose that transcription factors regulate chromatin structure at replication origins by recruiting chromatin-modifying proteins, such as HATs, to load the initiator.
Genetic association study of psychotic experiences in UK Biobank
Authors: Legge Sophie E. , Jones Hannah J. , Kendall Kimberley M. , Pardiñas Antonio F. , Menzies Georgina , Bracher-Smith Mathew , Escott-Price Valentina , Rees Elliott , Davis Katrina A.S. , Hotopf Matthew , Savage Jeanne E. , Posthuma Danielle , Holmans Peter , Kirov George , Owen Michael J. , O’Donovan Michael C. , Zammit Stanley , Walters James T.R.
Published: March 2019

Psychotic experiences, such as hallucinations and delusions, are reported by approximately 5%-10% of the general population, though only a small proportion of individuals develop psychotic disorders such as schizophrenia or bipolar disorder. Studying the genetic aetiology of psychotic experiences in the general population, and its relationship with the genetic aetiology of other disorders, may increase our understanding of their pathological significance. Using the population-based UK Biobank sample, we performed the largest genetic association study of psychotic experiences in individuals without a psychotic disorder. We conducted three genome-wide association studies (GWAS) for (i) any psychotic experience (6123 cases vs. 121,843 controls), (ii) distressing psychotic experiences (2143 cases vs. 121,843 controls), and (iii) multiple occurrence psychotic experiences (3337 cases vs. 121,843 controls). Analyses of polygenic risk scores (PRS), genetic correlation, and copy number variation (CNV) were conducted to assess whether genetic liability to psychotic experiences is shared with schizophrenia and/or other neuropsychiatric disorders and traits. GWAS analyses identified four loci associated with psychotic experiences including a locus in Ankyrin-3 (ANK3, OR=1.16,p=3.06 × 10−8) with any psychotic experience and a locus in cannabinoid receptor 2 gene (CNR2,OR=0.66,p=3.78×10−8) with distressing psychotic experiences. PRS analyses identified associations between psychotic experiences and genetic liability for schizophrenia, major depressive disorder, and bipolar disorder, and these associations were stronger for distressing psychotic experiences. Genetic correlation analysis identified significant genetic correlations between psychotic experiences and major depressive disorder, schizophrenia, autism spectrum disorder and a cross-disorder GWAS. Individuals reporting psychotic experiences had an increased burden of CNVs previously associated with schizophrenia (OR=2.04,p=2.49×10−4) and of those associated with neurodevelopmental disorders more widely (OR=1.75,p=1.41×10−3). In conclusion, we identified four genome-wide significant loci in the largest GWAS of psychotic experiences from the population-based UK Biobank sample and found support for a shared genetic aetiology between psychotic experiences and schizophrenia, but also major depressive disorder, bipolar disorder and neurodevelopmental disorders.
NRT2.1 phosphorylation prevents root high affinity nitrate uptake activity inArabidopsis thaliana
Authors: Jacquot Aurore , Chaput Valentin , Mauries Adeline , Li Zhi , Tillard Pascal , Fizames Cécile , Bonillo Pauline , Bellegarde Fanny , Laugier Edith , Santoni Véronique , Hem Sonia , Martin Antoine , Gojon Alain , Schulze Waltraud , Lejay Laurence
Published: March 2019

InArabidopsis thaliana,NRT2.1codes for a main component of the root nitrate high-affinity transport system. Previous studies revealed that post-translational regulation of NRT2.1 plays an important role in the control of root nitrate uptake and that one mechanism could correspond to NRT2.1 C-terminus processing. To further investigate this hypothesis, we produced transgenic plants with truncated forms of NRT2.1. It revealed an essential sequence for NRT2.1 activity, located between the residues 494-513. Using a phospho-proteomic approach, we found that this sequence contains one phosphorylation site, at serine 501, which can inactivate NRT2.1 function when mimicking the constitutive phosphorylation of this residue in transgenic plants. This phenotype could neither be explained by changes in abundance of NRT2.1 and NAR2.1, a partner protein of NRT2.1, nor by a lack of interaction between these two proteins. Finally, the relative level of serine 501 phosphorylation was found to be modulated by nitrate in wildtype plants. Altogether, these observations allowed us to propose a model for a new and essential mechanism for the regulation of NRT2.1 activity.
Tbet promotes NK cell egress from the bone marrow and CXCR6 expression in immature NK cells
Authors: Cuff Antonia O. , Perchet Thibaut , Dertschnig Simone , Golub Rachel , Male Victoria
Published: March 2019

Tbet-deficient mice have reduced NK cells in blood and spleen, but increased NK cells in bone marrow and lymph nodes, a phenotype that is thought to be due to defective migration. Here, we revisit the role of Tbet in NK cell bone marrow egress. We definitively show that the accumulation of NK cells in the bone marrow of Tbet-deficient (Tbx21-/-) animals occurs because of a cell-intrinsic migration defect. We identify a profile of gene expression, co-ordinated by Tbet, which affects the localisation of NK cells in the bone marrow. Tbet promotes Cxcr6 expression and immature NK cells accumulate in the bone marrow of CXCR6-deficient mice. This suggests that CXCR6 is among the mediators of migration, controlled by Tbet, that co-ordinate NK cell bone marrow egress.
Optimizing the power to identify the genetic basis of complex traits with Evolve and Resequence studies
Authors: Vlachos Christos , Kofler Robert
Published: March 2019

Evolve and Resequence (E&R) studies are frequently used to dissect the genetic basis of quantitative traits. By subjecting a population to truncating selection for several generations and estimating the allele frequency differences between selected and non-selected populations using Next Generation Sequencing, the loci contributing to the selected trait may be identified. The role of different parameters, such as, the population size or the number of replicate populations have been examined in previous works. However, the influence of the selection regime, i.e. the strength of truncating selection during the experiment, remains little explored. Using whole genome, individual based forward simulations of E&R studies, we found that the power to identify the causative alleles may be maximized by gradually increasing the strength of truncating selection during the experiment. Notably, such an optimal selection regime comes at no or little additional cost in terms of sequencing effort and experimental time. Interestingly, we also found that a selection regime which optimizes the power to identify the causative loci is not necessarily identical to a regime that maximizes the phenotypic response. Finally, our simulations suggest that an E&R study with an optimized selection regime may have a higher power to identify the genetic basis of quantitative traits than a GWAS, highlighting that E&R is a powerful approach for finding the loci underlying complex traits.
Dlx5andDlx6expression in GABAergic neurons controls behavior, metabolism, healthy aging and lifespan
Authors: de Lombares Camille , Heude Eglantine , Alfama Gladys , Fontaine Anastasia , Hassouna Rim , Vernochet Cécile , de Chaumont Fabrice , Olivo-Marin Christophe , Ey Elodie , Parnaudeau Sébastien , Tronche François , Bourgeron Thomas , Luquet Serge , Levi Giovanni , Narboux-Nême Nicolas
Published: March 2019

Dlx5andDlx6encode two homeobox transcription factors expressed by developing and mature GABAergic interneurons. During developmentDlx5/6are important for the differentiation ofParvalbumin(Pvalb)-expressing neurons. Perinatal lethality of homozygous mice in whichDlx5/6have been constitutively deleted has, so far, hindered the study of the function of these genes in adult neurons. We first show thatDlx5andDlx6are expressed by all subclasses of adult cortical GABAergic neurons. Then we analyseVgatΔDlx5-6mice in whichDlx5andDlx6are simultaneously inactivated in all GABAergic interneurons.VgatΔDlx5-6mice present a behavioral pattern suggesting reduction of anxiety and obsessive-compulsive activities. They rapidly access and spend more time in the central region of an open field, bury few marbles in the marble burying test and show little interest in nest building. Male and female 20-month-oldVgatΔDlx5-6animals have the same size as their normal littermates, but present a 25% body weight reduction associated with a marked decline in white and brown adipose tissue. Remarkably, bothVgatΔDlx5-6/+andVgatΔDlx5-6mice present a 33% longer median survival than their control littermates. Hallmarks of biological aging such as motility, adipose deposition and coat conditions are improved in mutant animals. Our data imply that GABAergic interneurons can regulate mammalian healthspan and lifespan throughDlx5/6-dependent mechanisms. Understanding these regulations can be an entry point to unravel the processes through which the brain affects body homeostasis and, ultimately, longevity and healthy aging.

SIGNIFICANCE STATEMENT

Dlx5 and Dlx6 are transcription factors controlling several developmental processes, including GABAergic neuronal migration and differentiation. To study their function in adult brain, we selectively inactivated both genes in GABAergic interneurons (VgatΔDlx5-6mice). Mutant mice have reduced anxiety-like and obsessive-compulsive behaviors. Interestingly,VgatΔDlx5-6mice have a 25% body weight reduction and about 70% less white and brown adipose tissue; their general health status is excellent.VgatΔDlx5-6mice have a median survival about 33% longer than their control littermates and hallmarks of biological aging are improved. Dlx5/6-dependent regulations in GABAergic neurons could be an entry point to understand how the brain determines the psychophysiological status of the body and, ultimately, longevity and healthy aging.
Detection of EGFR deletion using unique RepSeq technology
Authors: Vinayagamoorthy Thuraiayah , Qin Dahui , Ye Fei , Zhong Minghao
Published: March 2019

We are reporting a novel sequencing technology, RepSeq (Repetitive Sequence), that has high sensitivity, specificity and quick turn-around time. This new sequencing technology is developed by modifying traditional Sanger sequencing technology in several aspects. The first, a homopolymer tail is added to the PCR primer(s), which makes interpreting electropherograms a lot easier than that in traditional Sanger sequencing. The second, an indicator nucleotide is added at the 5’end of the homopolymer tail. In the presence of a deletion, the position of the indicator nucleotide in relation to the wild type confirms the deletion. At the same time, the indicator of the wild type serves as the internal control. Furthermore, the specific design of the PCR and/or sequencing primers will specifically enrich/select mutant alleles, which increases sensitivity and specificity significantly. Based on serial dilution studies, the analytical lower limit of detection was 1.47 copies. A total of 89 samples were tested for EGFR exon 19 deletion, of which 21 were normal blood samples and 68 were samples previously tested by either pyrosequencing or TruSeq Next Generation Sequencing Cancer Panel. There was 100 % concordance among all the samples tested. RepSeq technology has overcome the shortcomings of Sanger sequencing and offers an easy-to-use novel sequencing method for personalized precision medicine.
Nintedanib ameliorates experimental pulmonary arterial hypertension via inhibition of endothelial mesenchymal transition and smooth muscle cell proliferation
Authors: Tsutsumi Takeo , Nagaoka Tetsutaro , Yoshida Takashi , Wang Lei , Kuriyama Sachiko , Suzuki Yoshifumi , Nagata Yuichi , Harada Norihiro , Kodama Yuzo , Takahashi Fumiyuki , Morio Yoshiteru , Takahashi Kazuhisa
Published: March 2019

Neointimal lesion and medial wall thickness of pulmonary arteries (PAs) are common pathological findings in pulmonary arterial hypertension (PAH). Platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) signaling contribute to intimal and medial vascular remodeling in PAH. Nintedanib is a tyrosine kinase inhibitor whose targets include PDGF and FGF receptors. Although the beneficial effects of nintedanib were demonstrated for human idiopathic pulmonary fibrosis, its efficacy for PAH is still unclear. Thus, we hypothesized that nintedanib is a novel treatment for PAH to inhibit the progression of vascular remodeling in PAs. The inhibitory effects of nintedanib were evaluated both in endothelial mesenchymal transition (EndMT)-induced human pulmonary microvascular endothelial cells (HPMVECs) and human pulmonary arterial smooth muscle cells (HPASMCs) stimulated by growth factors. We also tested the effect of chronic nintedanib administration on a PAH rat model induced by Sugen5416 (a VEGF receptor inhibitor) combined with chronic hypoxia. Nintedanib was administered from weeks 3 to 5 after Sugen5416 injection, and pulmonary hemodynamics and PAs pathology were evaluated. Nintedanib attenuated the expression of mesenchymal markers in EndMT-induced HPMVECs and HPASMCs proliferation. Phosphorylation of PDGF and FGF receptors was augmented both in both intimal and medial lesions of PAs. Nintedanib blocked these phosphorylation, improved hemodynamics and reduced vascular remodeling involving neointimal lesions and medial wall thickening in PAs. Additionally, expressions Twist1, transcription factors associated with EndMT, in lung tissue was significantly reduced by nintedanib. These results suggest that nintedanib may be a novel treatment for PAH with anti-vascular remodeling effects.
Mate choice confers direct benefits to females ofAnastrepha fraterculus(Diptera: Tephritidae)
Authors: Bachmann Guillermo E. , Devescovi Francisco , Nussenbaum Ana L. , Milla Fabián H. , Shelly Todd E. , Cladera Jorge L. , Fernández Patricia C. , Vera María T. , Segura Diego F.
Published: March 2019

Exposure to plant compounds and analogues of juvenile hormone (JH) increase male mating success in several species of tephritid fruit flies. Most of these species exhibit a lek mating system, characterized by active female choice. Although the pattern of enhanced male mating success is evident, few studies have investigated what benefits, if any, females gain via choice of exposed males in the lek mating system. In the South American fruit fly,Anastrepha fraterculus, females mate preferentially with males that were exposed to volatiles released by guava fruit or treated with methoprene (a JH analogue). Here, we tested the hypothesis that female choice confers direct fitness benefits in terms of fecundity and fertility. We first carried out mate choice experiments presenting females with males treated and non-treated with guava volatiles or, alternatively, treated and non-treated with methoprene. After we confirm female preference for treated males, we compared the fecundity and fertility between females mated with treated males and non-treated ones. We found thatA. fraterculusfemales that mated with males exposed to guava volatiles showed higher fecundity than females mated to non-exposed males. On the other hand, females that mated methoprene-treated males showed no evidence of direct benefits. Our findings represent the first evidence of a direct benefit associated to female preference for males that were exposed to host fruit odors in tephritid fruit flies. Differences between the two treatments are discussed in evolutionary and pest management terms.
Advancements and forecasts of electronic tax return and informational filings in the US
Authors: Koong Kai S. , Bai Shuming , Tejinder Sara , Morris Charlotte
Published: March 2019

Purpose

The US Congress set the original goal that 80 per cent of all tax returns should to be filed electronically for the 2007 tax year. Unfortunately, only 70 per cent of the total returns were electronically filed (e-filed) in 2017. This paper aims to examine the longitudinal progress of total tax returns e-filed by individuals, businesses and “other” categories for the period from 2004 to 2017 and projects a timeline to attain the goal.

Design/methodology/approach

A comprehensive computation and analysis were performed for the volume, ratios and growth of e-filing for the major types of return. A parallel analysis was performed for the business categories. Applying various time series and exponential smoothing forecasting models, the authors projected major return e-filings for the forecast horizons from 2018 to 2025.

Findings

First, individual tax returns filed electronically have attained the target goal of 80 per cent since 2012, the extended deadline by Congress, so have corporations and partnerships for Fiscal Year 2017. Second, both the e-file volume and e-file rate for the grand total, individuals and businesses exhibit monotonically increasing trends over the sample period. Third, of the grand e-filings, individual returns constitute the vast majority of 84 per cent, while business e-files are less than 12 per cent.

Originality/value

This study is a holistic and comprehensive analysis of the adoption of e-filing in the USA. From the longitudinal analysis and the variety of forecasting models applied, the results show that the focus should be on the employment tax e-file as it stands at only 41 per cent for 2017 due to few mandates, while the returns make up 65 per cent of total business returns. The authors projected that the grand total e-filing will attain the Congressional goal of 80 per cent by 2020 along with proposed strategies and recommendations.
Earnings management and performance of management buyouts
Authors: Tutuncu Lokman
Published: March 2019

Purpose

The purpose of this paper is to examine the effect of pre-acquisition earnings management on the performance of private firm management buyouts.

Design/methodology/approach

The study examines 291 UK private firms acquired by their managers between 2004 and 2012. Earnings management is investigated by means of cross-sectional discretionary accruals models, and estimated discretionary accruals are regressed on performance changes in the three years following acquisition.

Findings

Management buyouts of private firms are preceded by earnings overstatement and followed by performance deterioration. Private equity sponsored firms engage less in earnings management and remain more profitable than non-sponsored buyouts. Upward earnings managers cease to outperform industry after second post-buyout year, while aggressive earnings managers do not outperform industry at all. Discretionary total accruals are inversely associated with performance changes in the three years after buyout, and explain over 4 per cent of the changes in performance.

Research limitations/implications

Pertinent to the utilisation of private firms and their exemption from publishing cash flow statement, the study relies on accrual-based models for tests of earnings management.

Originality/value

The paper contributes to the mergers and acquisitions literature and value creation debate in buyouts by providing the first tests of earnings management and post-acquisition performance in private firm management buyouts.
Investigating the mediating role of job embeddedness: evidence of Iranian context
Authors: Rahimnia Fariborz , Eslami Ghasem , Nosrati Saeid
Published: March 2019

Purpose

The purpose of this paper is to investigate the mediating role of job embeddedness in the relationship between perceived job security and perceived job flexibility and its impact on creative performance.

Design/methodology/approach

The statistical population of this study consisted of all employees at the Electricity Company of Mashhad, and a sample comprising 300 participants was finalized. In order to analyze the data, different statistical analysis methods were used, including Pearson’s correlation analysis and structural equation modeling.

Findings

The findings indicated that perceived job security has a positive impact on job embeddedness, while it has no significant impact on the employees’ creative performance. On the other hand, perceived job flexibility has a positive effect on both job embeddedness and creative performance. Moreover, the mediating role of job embeddedness was approved.

Originality/value

Since creative performance in this changeable environment becomes essential, identifying mechanisms which can embed employees to their company would bring about several positive consequences. Furthermore, little is known about the antecedents and potential consequences of job embeddedness, especially in developing countries.
GerminaR: An R package for germination analysis with the interactive web application “GerminaQuant for R”
Authors: Lozano‐Isla Flavio , Benites‐Alfaro Omar E. , Pompelli Marcelo F.
Published: March 2019

The germination process is one of the most sensitive stages in the early development of plants. The behavior and the responses of the plants in agronomic, biological and ecophysiological studies can be inferred through this process. However, the calculation of the germination variables is laborious. In this sense, the GerminaR package for the statistical software application R, which includes an interactive web application “GerminaQuant for R” for users without programming knowledge is presented. These tools should contribute greatly to improve analyses in germination studies.
Moving Beyond Semantics on Autonomous Weapons: Meaningful Human Control in Operation
Authors: Ekelhof Merel
Published: March 2019

Ongoing discussions about autonomous weapons typically share concerns of losing control and the potentially destabilizing consequences for global security. To the extent that there is any consensus among states, academics, NGOs and other commentators involved in diplomatic efforts under the auspices of the UN Convention on Certain Conventional Weapons, it is grounded in the idea that all weapons should be subject to meaningful human control. This intuitively appealing concept immediately gained traction, although at a familiar legal‐political cost: nobody knows what the concept actually means in practice. Although global discourses on policy and governance are typically infused with ambiguity, abstract concepts are of little use if they ignore the operational context that confronts the military in their application. This article places this intuitively appealing concept in context, and thus examines it in operational practice. Paying attention to this military practice is important as it demonstrates that meaningful human control is not the only, or the best, approach through which to characterize the human role and govern the challenges raised by autonomous weapons.
Enablers and Barriers of Tourism as a Driver of Economic and Social‐cultural Growth in Remote Queensland
Authors: Summers Jane , Cavaye Jim , Woolcock Geoffrey
Published: March 2019

Regional and remote tourism in Australia is characterised by micro‐, small‐ and medium‐sized businesses, spatially dispersed and fragmented. Characteristics which present unique challenges for these communities attempting to develop tourism as a way of diversifying their economy. This study explored the views and experiences from residents and businesses in six remote local government areas in South Western Queensland to identify the barriers and enablers for remote communities to using tourism as a driver of economic and social‐cultural growth. We found a lack of understanding of the structure and behaviour of the tourism industry; a lack of business acumen; a lack of financial and human resources; and a reluctance to collaborate by tourism businesses to be barriers to tourism‐led economic growth. Enablers to tourism led growth included: local government support for tourism development; a sound understanding of the mechanics and structure of the tourism industry; and the capacity to engage in marketing that captured and narrated the visitor experience in digital channels.
Impact of age on the discriminative ability of an emergency triage system: A cohort study
Authors: Kuriyama Akira , Ikegami Tetsunori , Nakayama Takeo
Published: March 2019

Background

Emergency triage systems optimize resources in emergency departments (EDs) for those who need urgent care. Five–level triage systems, such as the Canadian Triage and Acuity Scale (CTAS), have been used worldwide. We examined whether the discriminative ability of an emergency triage system varies according to age group using a patient cohort triaged with the Japan Triage and Acuity Scale (JTAS), a validated system based on the CTAS.

Methods

We conducted a cohort study of 27 120 self–presenting patients aged 16 years and older who were triaged with (JTAS) between June 2013 and May 2014 at a Japanese tertiary care hospital. Outcome measures were admission to intensive care units (ICUs) as the primary and in‐hospital death as the secondary. We described the trends of the discriminative ability of JTAS using areas under the curve of the receiver operating characteristic (AUROC), sensitivity, specificity, positive predictive value, and negative predictive value of JTAS for seven age categories.

Results

The AUROC of JTAS for ICU admission decreased with age (maximum 0.85 to minimum 0.71), sensitivity non‐significantly decreased (maximum 0.67 to minimum 0.32), and specificity declined with age (maximum 0.96 to minimum 0.88). The positive and negative predictive value increased (minimum 0.03 to maximum 0.09) and decreased (minimum 0.98 to maximum 0.99), respectively, with age. Overall misclassification increased across age groups (P < 0.001). This trend was mostly consistent with the analysis of in‐hospital death.

Conclusion

Our study suggests that the discriminative ability of an emergency triage system decreases as patient age increases, corresponding to a decrease in specificity. Undertriage may not significantly increase, but misclassification significantly increases as patient age increases.
Chronic kidney disease and acute kidney injury in arthroplasty patients over 65 years of age
Authors: Nikkinen Okke , Nieminen Teemu , Alahuhta Seppo , Ohtonen Pasi , Vakkala Merja
Published: March 2019

Background

The purpose of this study was to evaluate the prevalence of chronic kidney disease (CKD) and the incidence of perioperative acute kidney injury (AKI) in primary arthroplasty patients over 65 years of age. Risk factors, perioperative events and the outcome of surgery were evaluated.

Methods

This retrospective, hospital register‐based study consists of patients operated in 2014 in the area of Oulu, Finland. The estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration formula. The incidence of AKI was evaluated based on the serum creatinine criteria of the KDIGO (Kidney Disease, Improving Global Outcomes) classification.

Results

Of the 807 patients, 60.8% had mildly decreased (60‐89 ml/min/1.73 m2) and 13.5% moderately to severely decreased eGFR (<60 ml/min/1.73 m2) preoperatively. Only 33.9% of patients with an eGFR < 60 ml/min/1.73 m2 had a diagnosis of a kidney disease. In emergencies, 46.9% of patients with an eGFR < 60 ml/min/1.73 m2 were deceased at the 12‐month follow‐up point. The measurement of postoperative sCr was not complete (477/807) and was allocated to emergencies and older patient with more comorbidities. Of those whose postoperative sCr was available, 14 (2.9%) fulfilled AKI criteria. Most of the AKI cases had a decrease in eGFR preoperatively, a diagnosed kidney disease or diabetes mellitus.

Conclusions

Impairment of kidney function was common and was related to mortality in emergency arthroplasties. Measurements of postoperative sCr were allocated to high risk patients. Preoperative kidney function, kidney disease and diabetes mellitus were important determinants for perioperative AKI.
Exports and governance: the role of private voluntary agrifood standards
Authors: Fiankor Dela‐Dem Doe , Martínez‐Zarzoso Inmaculada , Brümmer Bernhard
Published: March 2019

The empirical evidence that institutional differences across countries affect bilateral trade is robust. The crucial question remains how countries can enhance trade amid these differences. In this article, we measure the degree to which governance and institutions differ between countries as “governance distance.” Using a sample of EU/EFTA imports, we examine how adopting private agrifood safety standards modify the effect of governance distance on exports of fruits and vegetables, in particular apples, bananas, and grapes, within a structural gravity framework. Our results show that while increasing governance distance hinders bilateral trade, the interaction of standards and the governance distance is positively associated with exports, hence partially offsetting the direct trade‐inhibiting effects of the latter. GlobalGAP certified countries see the trade‐inhibiting effects of governance distance on their exports reduced by about 50%, ceteris paribus.