bluuebunny/crossref_metadata_2025 huggingface dataset:
Multi-Method Molecular Characterisation of Human Dust-Mite-associated Allergic Asthma
Authors: Whittle E. , Leonard M.O. , Gant T.W. , Tonge D.P
Published: October 2018

Asthma is a chronic inflammatory disorder of the airways. Disease presentation varies greatly in terms of cause, development, severity, and response to medication, and thus the condition has been subdivided into a number of asthma phenotypes. There is still an unmet need for the identification of phenotype-specific markers and accompanying molecular tools that facilitate the classification of asthma phenotype. To this end, we utilised a range of molecular tools to characterise a well-defined group of adults with poorly controlled asthma associated with house dust mite (HDM) allergy, relative to non-asthmatic control subjects. Circulating messenger RNA (mRNA) and microRNA (miRNA) were sequenced and quantified, and a differential expression analysis of the two RNA populations performed to determine how gene expression and regulation varied in the disease state. Further, a number of circulating proteins (IL-4, 5, 10, 17A, Eotaxin, GM-CSF, IFNy, MCP-1, TARC, TNFa, Total IgE, and Endotoxin) were quantified to determine whether the protein profiles differed significantly dependent on disease state. Finally, assessment of the circulating “blood microbiome” was performed using 16S rRNA amplification and sequencing. Asthmatic subjects displayed a range of significant alterations to circulating gene expression and regulation, relative to healthy control subjects, that may influence systemic immune activity. Notably, several circulating mRNAs were detected in the plasma in a condition-specific manner, and many more were found to be expressed at altered levels. Proteomic analysis revealed increased levels of inflammatory proteins within the serum, and decreased levels of the bacterial endotoxin protein in the asthma state. Comparison of blood microbiome composition revealed a significant increase in the Firmicutes phylum with asthma that was associated with a concomitant reduction in the Proteobacteria phylum. This study provides a valuable insight into the systemic changes evident in the HDM-associated asthma, identifies a range of molecules that are present in the circulation in a condition-specific manner (with clear biomarker potential), and highlights a range of hypotheses for further study.
Interaction of modified oligonucleotides with nuclear proteins, formation of novel nuclear structures and sequence-independent effects on RNA processing
Authors: Flynn Loren L , Li Ruohan , Aung-Htut May T , Pitout Ianthe L , Cooper Jack A L , Hubbard Alysia , Griffiths Lisa , Bond Charlie , Wilton Steve D , Fox Archa H , Fletcher Sue
Published: October 2018

Oligonucleotides and nucleic acid analogues that alter gene expression are showing therapeutic promise for selected human diseases. The modification of synthetic nucleic acids to protect against nuclease degradation and to influence drug function is common practice, however, such modifications may also confer unexpected physicochemical and biological properties. Here we report backbone-specific effects of modified oligonucleotides on subnuclear organelles, altered distribution of nuclear proteins, the appearance of novel structured nuclear inclusions, and modification of RNA processing in cultured cells transfected with antisense oligonucleotides on a phosphorothioate backbone. Phosphodiester and phosphorodiamidate morpholino oligomers elicited no such consequences. Disruption of subnuclear structures and proteins elicit severe phenotypic disturbances, revealed by transcriptomic analysis of fibroblasts exhibiting such disruption. These data suggest that the toxic effects and adverse events reported after clinical evaluation of phosphorothioate nucleic acid drugs may be mediated, at least in part, by non-specific interaction of nuclear components with the phosphorothioate backbone.
Ocular disease mechanisms elucidated by genetics of human fetal retinal pigment epithelium gene expression
Authors: Liu Boxiang , Calton Melissa A. , Abell Nathan S. , Benchorin Gillie , Gloudemans Michael J. , Chen Ming , Hu Jane , Li Xin , Balliu Brunilda , Bok Dean , Montgomery Stephen B. , Vollrath Douglas
Published: October 2018

The eye is an intricate organ with limited representation in large-scale functional genomics datasets. The retinal pigment epithelium (RPE) serves vital roles in ocular development and retinal homeostasis. We interrogated the genetics of gene expression of cultured human fetal RPE (fRPE) cells under two metabolic conditions. Genes with disproportionately high fRPE expression are enriched for genes related to inherited ocular diseases. Variants near these fRPE-selective genes explain a larger fraction of risk for both age-related macular degeneration (AMD) and myopia than variants near genes enriched in 53 other human tissues. Increased mitochondrial oxidation of glutamine by fRPE promoted expression of lipid synthesis genes implicated in AMD. Expression and splice quantitative trait loci (e/sQTL) analysis revealed shared and metabolic condition-specific loci of each type and several eQTL not previously described in any tissue. Fine mapping of fRPE e/sQTL across AMD and myopia genome-wide association data suggests new candidate genes, and mechanisms by which the same common variant of RDH5 contributes to both increased AMD risk and decreased myopia risk. Our study highlights the unique transcriptomic characteristics of fRPE and provides a resource to connect e/sQTL in a critical ocular cell type to monogenic and complex eye disorders.
Automatic Single-Cell Discrimination by Cellular Appearance using Convolutional Neural Network
Authors: Matsuoka Yoshikazu , Nakatsuka Ryusuke , Fujioka Tatsuya
Published: October 2018

Morphological images of cells contain extensive information, which help biologists to infer the type and state of cells to some degree based on their morphology. Convolutional Neural Network, a neural network architecture, is a powerful tool used for image recognition. However, whether it can be used to classify cells on the basis of their morphology remains unclear. In this study, we demonstrate that 10 different hematopoietic tumor cell lines with similar morphologies that biologists find difficult to distinguish can be classified with >90% accuracy using only their bright-field images when analyzed using a Convolutional Neural Network. This novel and simple system using bright-field images of cells could be a powerful analytical tool for cell type discrimination and could also be applied to the clinical diagnoses of hematopoietic tumors.
Structure and genome ejection mechanism of Podoviridae phage P68 infecting Staphylococcus aureus
Authors: Hrebík Dominik , Štveráková Dana , Škubník Karel , Füzik Tibor , Pantůček Roman , Plevka Pavel
Published: October 2018

Phages infecting S. aureus have the potential to be used as therapeutics against antibiotic-resistant bacterial infections. However, there is limited information about the mechanism of genome delivery of phages that infect Gram-positive bacteria. Here we present the structures of S. aureus phage P68 in its native form, genome ejection intermediate, and empty particle. The P68 head contains seventy-two subunits of inner core protein, fifteen of which bind to and alter the structure of adjacent major capsid proteins and thus specify attachment sites for head fibers. Unlike in the previously studied phages, the head fibers of P68 enable its virion to position itself at the cell surface for genome delivery. P68 genome ejection is triggered by disruption of the interaction of one of the portal protein subunits with phage DNA. The inner core proteins are released together with the DNA and enable the translocation of phage genome across the bacterial membrane into the cytoplasm.
The molecular genetics of hand preference revisited
Authors: de Kovel Carolien G.F. , Francks Clyde
Published: October 2018

Hand preference is a prominent behavioural trait linked to human brain asymmetry. A handful of genetic variants have been reported to associate with hand preference or quantitative measures related to it. Most of these reports were on the basis of limited sample sizes, by current standards for genetic analysis of complex traits. Here we performed a genome-wide association analysis of hand preference in the large, population-based UK Biobank cohort (N=331,037). We used gene-set enrichment analysis to investigate whether genes involved in visceral asymmetry are particularly relevant to hand preference, following one previous report. We found no evidence implicating any specific candidate variants previously reported. We also found no evidence that genes involved in visceral laterality play a role in hand preference. It remains possible that some of the previously reported genes or pathways are relevant to hand preference as assessed in other ways, or else are relevant within specific disorder populations. However, some or all of the earlier findings are likely to be false positives, and none of them appear relevant to hand preference as defined categorically in the general population. Within the UK Biobank itself, a significant association implicates the geneMAP2in handedness.
Parallel systems for sound processing and functional connectivity among layer 5 and 6 auditory corticothalamic neurons
Authors: Williamson Ross S. , Polley Daniel B.
Published: October 2018

Cortical layers (L) 5 and 6 are populated by a spatially intermingled menagerie of neurons with distinct inputs and downstream targets. Here, we made optogenetically guided recordings from L5 and L6 corticothalamic (CT) neurons in the mouse auditory cortex to discern underlying patterns of functional connectivity and sensory processing in the largest sub-cerebral projection system. Whereas L5 CT neurons showed broad stimulus selectivity with sluggish response latencies and extended temporal non-linearities, L6 CTs exhibited sparse sound feature selectivity and rapid temporal processing. L5 CT spikes lagged behind neighboring units and imposed weak feedforward excitation within the local column. By contrast, L6 CT spikes drove robust and sustained activity in neighboring units. Our findings underscore a duality among CT projection neurons, where L5 CT units are canonical broadcast neurons that integrate sensory inputs for transmission to distributed downstream targets, while L6 CT neurons are positioned to regulate thalamocortical response gain and selectivity.
Managing river fish biodiversity generates substantial economic benefits in four European countries
Authors: Riepe Carsten , Meyerhoff Jürgen , Fujitani Marie , Fujitani Marie , Aas Øystein , Radinger Johannes , Kochalski Sophia , Arlinghaus Robert
Published: October 2018

Ecosystems and biodiversity produce benefits to society, but many of them are hard to quantify. For example, it is unclear whether European societies gain benefits from experiencing rivers that host high native biodiversity. Without such knowledge, monetary investments into ecologically oriented river management plans are difficult to justify. The objective of this study was to reveal how the public in four European countries values ecological characteristics of domestic rivers and the outcomes of hypothetical river basin management plans designed to improve river ecosystems, particularly fish biodiversity. We conducted a choice experiment among the populations in Norway, Sweden, Germany and France. We found similar preference structures in all countries with high marginal willingness-to-pay for improvements of abiotic river attributes (increased accessiblity of the river banks, improved bathing water quality, decreased river fragmentation). Citizens also benefited from certain fish species occurring in a river with native salmonid species being more valued than nonnatives, particularly in Norway, and from the degree of a river’s native biodiversity. Welfare measures calculated for selected river basin management plans (policy scenarios) revealed societal benefits that were primarily derived from ecological river management whereas a scenario focusing on hydroelectricity production generated the lowest utility. We conclude that ecological river management may produce high nonmarket economic benefits in all study countries, particularly through the management of abiotic river attributes and the restoration of declining or extinct fish species. Our results help to inform decisions on restoration efforts by showcasing the benefits that these measures have for the public.
Quantitative Proteomic Analysis of Prostate Tissue Specimens Identifies Deregulated Protein Complexes in Primary Prostate Cancer
Authors: Zhou Bo , Yan Yiwu , Wang Yang , You Sungyong , Freeman Michael R. , Yang Wei
Published: October 2018

Prostate cancer (PCa) is the most frequently diagnosed non-skin cancer and a leading cause of mortality among males in developed countries. However, our understanding of the global changes of protein complexes within PCa tissue specimens remains very limited, although it has been well recognized that protein complexes carry out essentially all major processes in living organisms and that their deregulation drives the pathogenesis and progression of various diseases. By coupling tandem mass tagging-synchronous precursor selection-mass spectrometry/mass spectrometry/mass spectrometry (TMT-SPSMS3) with differential expression and co-regulation analyses, the present study compared the differences between protein complexes in normal prostate, low-grade PCa, and high-grade PCa tissue specimens. Globally, a large downregulated putative protein-protein interaction (PPI) network was detected in both low-grade and high-grade PCa, yet a large upregulated putative PPI network was only detected in high-grade but not low-grade PCa, compared with normal controls. To identify specific protein complexes that are deregulated in PCa, quantified proteins were mapped to protein complexes in CORUM, a collection of experimentally verified mammalian protein complexes. Differential expression analysis suggested that mitochondrial ribosomes and the fibrillin-associated protein complex were significantly overexpressed, whereas the ITGA6-ITGB4-Laminin10/12 and the P2X7 receptor signaling complexes were significantly downregulated, in PCa compared with normal prostate. Moreover, differential co-regulation analysis indicated that the assembly levels of some nuclear protein complexes involved in RNA synthesis and processing were significantly increased in low-grade PCa, and those of mitochondrial complex I and its subcomplexes were significantly increased in high-grade PCa, compared with normal prostate. In summary, the study represents the first global and quantitative comparison of protein complexes in prostate tissue specimens. It is expected to enhance our understanding of the molecular mechanisms underlying PCa development and progression in human patients, as well as lead to the discovery of novel biomarkers and therapeutic targets for precision management of PCa.
Evolutionary couplings detect side-chain interactions
Authors: Hockenberry Adam J. , Wilke Claus O.
Published: October 2018

Patterns of amino acid covariation in large protein sequence alignments can inform the prediction of de novo protein structures, binding interfaces, and mutational effects. While algorithms that detect these so-called evolutionary couplings between residues have proven useful for practical applications, less is known about how and why these methods perform so well, and what insights into biological processes can be gained from their application. Evolutionary coupling algorithms are commonly benchmarked by comparison to true structural contacts derived from solved protein structures. However, the methods used to determine true structural contacts are not standardized and different definitions of structural contacts may have important consequences for interpreting the results from evolutionary coupling analyses and understanding their overall utility. Here, we show that evolutionary coupling analyses are significantly more likely to identify structural contacts between side-chain atoms than between backbone atoms. We use both simulations and empirical analyses to highlight that purely backbone-based definitions of true residue–residue contacts (i.e., based on the distance between Cα atoms) may underestimate the accuracy of evolutionary coupling algorithms by as much as 40% and that a commonly used reference point (Cβ atoms) underestimates the accuracy by 10–15%. These findings show that co-evolutionary outcomes differ according to which atoms participate in residue–residue interactions and suggest that accounting for different interaction types may lead to further improvements to contact-prediction methods.

Significance Statement

Evolutionary couplings between residues within a protein can provide valuable information about protein structures, protein-protein interactions, and the mutability of individual residues. However, the mechanistic factors that determine whether two residues will co-evolve remains unknown. We show that structural proximity by itself is not sufficient for co-evolution to occur between residues. Rather, evolutionary couplings between residues are specifically governed by interactions between side-chain atoms. By contrast, intramolecular contacts between atoms in the protein backbone display only a weak signature of evolutionary coupling. These findings highlight that different types of stabilizing contacts exist within protein structures and that these types have a differential impact on the evolution of protein structures that should be considered in co-evolutionary applications.
Optical Sectioning of Live Mammal with Near-Infrared Light Sheet
Authors: Wang Feifei , Wan Hao , Yue Jingying , Zhang Mingxi , Ma Zhuoran , Sun Qinchao , Qu Liangqiong , Ma Huilong , Zhong Yeteng , Tian Ye , Hong Guosong , Jung Li Wen , Liang Yongye , Liu Lianqing , Dai Hongjie
Published: October 2018

Deep-tissue three-dimensional optical imaging of live mammals in vivo with high spatiotemporal resolution in non-invasive manners has been challenging due to light scattering. Here, we developed near-infrared (NIR) light sheet microscopy (LSM) with optical excitation and emission wavelengths up to ~ 1320 nm and ~ 1700 nm respectively, far into the NIR-II (1000-1700 nm) region for 3D optical sectioning through live tissues. Suppressed scattering of both excitation and emission photons allowed one-photon optical sectioning at ~ 2 mm depth in highly scattering brain tissues. NIR-II LSM enabled non-invasive in vivo imaging of live mice, revealing never-before-seen dynamic processes such as highly abnormal tumor microcirculation, and 3D molecular imaging of an important immune checkpoint protein, programmed-death ligand 1 (PD-L1) receptors at the single cell scale in tumors. In vivo two-color near-infrared light sheet sectioning enabled simultaneous volumetric imaging of tumor vasculatures and PD-L1 proteins in live mammals.
Epigenome-wide association analysis of daytime sleepiness in the Multi-Ethnic Study of Atherosclerosis reveals African-American specific associations
Authors: Barfield Richard , Wang Heming , Liu Yongmei , Brody Jennifer A , Swenson Brenton , Li Ruitong , Bartz Traci M. , Sotoodehnia Nona , Chen Yii-der I. , Cade Brian E. , Chen Han , Patel Sanjay R. , Zhu Xiaofeng , Gharib Sina A. , Johnson W. Craig , Rotter Jerome I. , Saxena Richa , Purcell Shaun , Lin Xihong , Redline Susan , Sofer Tamar
Published: October 2018

Study Objectives

Excessive daytime sleepiness (EDS) is a consequence of inadequate sleep, or of a primary disorder of sleep-wake control. Population variability in prevalence of EDS and susceptibility to EDS are likely due to genetic and biological factors as well as social and environmental influences. Epigenetic modifications (such as DNA methylation-DNAm) are potential influences on a range of health outcomes. Here, we explored the association between DNAm and daytime sleepiness quantified by the Epworth Sleepiness Scale (ESS).

Methods

We performed multi-ethnic and ethnic-specific epigenome-wide association studies for DNAm and ESS in 619 individuals from the Multi-Ethnic Study of Atherosclerosis. Replication was assessed in the Cardiovascular Health Study (CHS). Genetic variants in genes proximal to ESS-associated DNAm were analyzed to identify methylation quantitative trait loci and followed with replication of genotype-sleepiness associations in the UK Biobank.

Results

61 methylation sites were associated with ESS (FDR ≤ 0.1) in African Americans only, including an association inKCTD5, a gene strongly implicated in sleep. One association (cg26130090) replicated in CHS African Americans (p-value 0.0004). We identified a sleepiness-associated methylation site in the geneRAI1, a gene associated with sleep and circadian phenotypes. In a follow-up analysis, a genetic variant withinRAI1associated with both DNAm and sleepiness score. The variant’s association with sleepiness was replicated in the UK Biobank.

Conclusions

Our analysis identified methylation sites in multiple genes that may be implicated in EDS. These sleepiness-methylation associations were specific to African Americans. Future work is needed to identify mechanisms driving ancestry-specific methylation effects.

Statement of Significance

Excessive daytime sleepiness is associated with negative health outcomes such as reduction in quality of life, increased workplace accidents, and cardiovascular mortality. There are race/ethnic disparities in excessive daytime sleepiness, however, the environmental and biological mechanisms for these differences are not yet understood. We performed an association analysis of DNA methylation, measured in monocytes, and daytime sleepiness within a racially diverse study population. We detected numerous DNA methylation markers associated with daytime sleepiness in African Americans, but not in European and Hispanic Americans. Future work is required to elucidate the pathways between DNA methylation, sleepiness, and related behavioral/environmental exposures.
Geometrical structure of perceptual color space: mental representations and adaptation invariance
Authors: Ennis Robert J , Zaidi Qasim
Published: October 2018

A central issue in neuroscience is to understand how the brain builds structured representations of percepts that facilitate useful inferences about the world. Similarity between percepts is used to accomplish many everyday tasks, e.g. object identification, so is widely used to construct geometrical spaces that represent stimulus qualities, but the intrinsic validity of the geometry is not tested critically. We introduce an experimental approach to equating relative similarities by setting perceived midpoints between pairs of stimuli. Midpoint settings are used with Varignon’s Theorem to test the intrinsic geometry of a representation space, and its mapping to a physical space of stimuli. For perceptual color space, we demonstrate that geometrical structure depends on the mental representation used in judging similarity: an affine geometry is valid only when observers use an opponent-color mental representation. An affine geometry implies that similarity can be judged within straight lines and across parallel lines, and its neural coding could involve ratios of responses. We show that this perceptual space is invariant to changes in illumination color, providing a formal justification to generalize to all of color space, color constancy results measured for color categories. Our midpoint measurements deviate significantly from midpoints in the “uniform” color spaces CIELAB and CIELUV, used extensively in industry and research, so these spaces do not provide adequate metric representation of perceived colors. Our paradigm can thus test for intrinsic geometrical assumptions underlying the representation space for many perceptual modalities, and for the extrinsic perceptual geometry of the space of physical stimuli.

Significance

Mathematical spaces based on similarity judgments are widely used to represent stimulus qualities in perception, cognition and neuroscience. We introduce a perceptual approach to equate relative similarities, and use them to test the geometry of a perceptual space and its mapping to a physical space of stimuli. For color perception, our results show that perceptual geometry depends on the mental representation used in judging similarity, and it has an affine structure when observers use an opponent-color representation. An affine geometry implies that neural coding of similarity could involve simple ratios of responses. Our measurements also reveal that the uniform color spaces CIELAB and CIELUV, used extensively in industrial applications, do not provide adequate representation of similarity between moderately spaced colors.
scFTD-seq: freeze-thaw lysis based, portable approach toward high-quality distributed single-cell 3’ mRNA profiling
Authors: Dura Burak , Choi Jin-Young , Zhang Kerou , Damsky William , Thakral Durga , Bosenberg Marcus , Craft Joe , Fan Rong
Published: October 2018

Cellular barcoding of 3’ mRNAs enabled massively parallel profiling of single-cell gene expression and has been implemented in droplet and microwell based platforms. The latter further adds the value for compatibility with low input samples, optical imaging, scalability, and portability. However, cell lysis in microwells remains suboptimal despite the recently developed sophisticated solutions. Here, we present scFTD-seq, a microchip platform for performingsingle-cellfreeze-thaw lysisdirectly toward 3’ mRNAsequencing. It offers format flexibility with a simplified, widely adoptable workflow that reduces the number of preparation steps and hands-on time, with the quality of data and the cost per sample matching that of the state-of-the-art scRNA-seq platforms. Freeze-thaw, known as an unfavorable lysis method resulting in possible RNA fragmentation, turns out to be fully compatible with single-cell 3’ mRNA sequencing, which detects only ~50 bases at the 3’ end. We applied it to the profiling of mixed populations including whole tumors for distinguishing all major cell types and to the profiling of circulating follicular helper T cells implicated in systemic lupus erythematosus pathogenesis. Our results delineate the heterogeneity in the transcriptional programs and effector functions of these rare pathogenic T cells. As scFTD-seq decouples on-chip cell isolation and the following library preparation steps, we envision it to potentially allow the sampling (capture of cells/beads in microwells) at the distributed sites including small clinics or point-of-care settings and downstream processing at a centralized facility, which should enable wide-spread adoption beyond academic laboratories – for any users even with no experience in scRNA-seq library generation.
A screen of 1,049 schizophrenia and 30 Alzheimer’s-associated variants for regulatory potential
Authors: Myint Leslie , Wang Ruihua , Boukas Leandros , Hansen Kasper D. , Goff Loyal A. , Avramopoulos Dimitrios
Published: October 2018

Recent genome-wide association studies (GWAS) identified numerous schizophrenia (SZ) and Alzheimer’s disease (AD) associated loci, most outside protein-coding regions and hypothesized to affect gene transcription. We used a massively parallel reporter assay (MPRA) to screen, 1,049 SZ and 30 AD variants in 64 and 9 loci respectively for allele differences in driving reporter gene expression. A library of synthetic oligonucleotides assaying each allele 5 times was transfected into K562 chronic myelogenous leukemia lymphoblasts and SK-SY5Y human neuroblastoma cells. 148 variants showed allelic differences in K562 and 53 in SK-SY5Y cells, on average 2.6 variants per locus. Nine showed significant differences in both lines, a modest overlap reflecting different regulatory landscapes of these lines that also differ significantly in chromatin marks. Eight of nine were in the same direction. We observe no preference for risk alleles to increase or decrease expression. We find a positive correlation between the number of SNPs in Linkage Disequilibrium (LD) and the proportion of functional SNPs supporting combinatorial effects that may lead to haplotype selection. Our results prioritize future functional follow up of disease associated SNPs to determine the driver GWAS variant(s), at each locus and enhance our understanding of gene regulation dynamics.
Massively scalable genetic analysis of antibody repertoires
Authors: Briney Bryan , Burton Dennis R.
Published: October 2018

With technical breakthroughs in the throughput and read-length of next-generation sequencing platforms, antibody repertoire sequencing is becoming an increasingly important tool for detailed characterization of the immune response. There is a need for open, scalable software for the genetic analysis of repertoire-scale antibody sequence data. To address this gap, we have developed the ab[x] package of software tools. There are three core components of the ab[x] toolkit, all of which are freely available: abcloud (github.com/briney/abcloud) for deployment and management of computational resources on Amazon’s Elastic Compute Cloud; abstar (github.com/briney/abstar) for pre-processing, germline gene assignment and primary annotation of antibody sequence data; and abutils (github.com/briney/abutils), which provides utilities for interactive downstream analysis of antibody repertoire data.
Side chain to main chain hydrogen bonds stabilize a polyglutamine helix in the activation domain of a transcription factor
Authors: Escobedo Albert , Topal Busra , Achim Kunze Micha Ben , Aranda Juan , Chiesa Giulio , Mungianu Daniele , Bernardo-Seisdedos Ganeko , Eftekharzadeh Bahareh , Gairí Margarida , Pierattelli Roberta , Felli Isabella C. , Diercks Tammo , Millet Oscar , García Jesús , Orozco Modesto , Crehuet Ramon , Lindorff-Larsen Kresten , Salvatella Xavier
Published: October 2018

Polyglutamine (polyQ) tracts are regions of low sequence complexity of variable length found in more than one hundred human proteins. These tracts are frequent in activation domains of transcription factors and their length often correlates with transcriptional activity. In addition, in nine proteins, tract elongation beyond specific thresholds causes polyQ disorders. To study the structural basis of the association between tract length, transcriptional activity and disease, here we addressed how the conformation of the polyQ tract of the androgen receptor (AR), a transcription factor associated with the polyQ disease spinobulbar muscular atrophy (SBMA), depends on its length. We found that the tract folds into a helical structure stabilized by unconventional hydrogen bonds between glutamine side chains and main chain carbonyl groups. These bonds are bifurcate with the conventional main chain to main chain hydrogen bonds stabilizing α-helices. In addition, since tract elongation provides additional interactions, the helicity of the polyQ tract directly correlates with its length. These findings suggest a plausible rationale for the association between polyQ tract length and AR transcriptional activity and have implications for establishing the mechanistic basis of SBMA.
Comparative analysis ofStreptococcusgenomes
Authors: Shelyakin Pavel V , Bochkareva Olga O , Karan Anna A , Gelfand Mikhail S
Published: October 2018

Background

Genome sequencing of multiple strains demonstrated high variability in gene content even in closely related strains of the same species and created a newly emerged object for genomic analysis, the pan-genome, that is, the complete set of genes observed in a given species or a higher level taxon. Here we analysed the pan-genome structure and the genome evolution of 25 strains ofStreptococcus suis, 50 strains ofStreptococcus pyogenesand 28 strains ofStreptococcus pneumoniae.

Results

Fractions of the pan-genome, unique, periphery, and universal genes differ in size, functional composition, the level of nucleotide substitutions, and predisposition to horizontal gene transfer and genomic rearrangements. The density of substitutions in intergenic regions appears to be correlated with selection acting on adjacent genes, implying that more conserved genes tend to have more conserved regulatory regions. The total pan-genome of the genus is open, but only due to strain-specific genes, whereas other pan-genome fractions reach saturation. The strain-specific fraction is enriched with mobile elements and hypothetical proteins, but also contains a number of candidate virulence-related genes, so it may have a strong impact on adaptability and pathogenicity.

About 7% of single-copy periphery genes have been found in different syntenic regions. More than a half of these genes are rare in allStreptococcusspecies; others are rare in at least one species. We have identified the set of genes with phylogenies inconsistent with species and non-conserved location in the chromosome; these genes are candidates for horizontal transfer between species.

An inversion of length 15 kB found in four independent branches ofS. pneumoniaehas breakpoints formed by genes encoding a surface antigen protein (PhtD). The observed parallelism may indicate the action of an antigen variation mechanism.

Conclusions

Members of the genusStreptococcushave a highly dynamic, open pan-genome, that potentially confers them with the ability to adapt to changing environmental conditions, i.e. antibiotic resistance or transmission between different hosts. Hence, understanding of genome evolution is important for the identification of potential pathogens and design of drugs and vaccines.
Whole blood and hypertonic saline resuscitation improve the outcomes of controlled hemorrhagic shock combined with penetrating brain injury in rat
Authors: Weissmann Marina , Dar Dalit , Krausz Michael
Published: October 2018

One of the most frequent injury patterns leading to early death of polytraumatized patients is hemorrhagic shock combined with traumatic brain injury. Currently, there is no agreement on the best treatment protocol of such injury. This study was aimed to compare the outcomes of resuscitation with various volumes of hypertonic saline (HTS), whole blood (WB) and fresh frozen plasma (FFP) in a rat model of penetrating brain injury combined with controlled hemorrhagic shock in order to look for optimal treatment. Anesthetized rats were intubated and ventilated. 30% of circulating blood volume was withdrawn following open brain injury, and intravenous resuscitation with various volumes of HTS, WB and FFP (3, 9, and 18 ml/kg) was administered. Blood samples were collected during the experiment for measurements of lactate and base excess levels, and before sacrifice for neutrophil counts. Twenty four and 48 hours after the injury, rat’s neurological status was examined. Rats were, then, sacrificed and pathological studies of brain and lung sections were performed. Regardless of fluid type, resuscitation improved the mean arterial pressure and lactate levels in accordance to fluid's volume. However, base excess was improved only when rats were treated with WB and FFP. Improvement in behavioral performance of the rats was observed when treated with 3 and 9 ml/kg HTS or with 18 ml/kg WB or FFP. Blood and lung neutrophils were reduced in rats treated with 9 or 18 ml/kg WB. Mortality rates were reduced in rats administered with 9 and 18 ml/kg of HTS or WB. Taken together, resuscitation with WB at 9-18ml/kg or HTS at 9ml/kg is optimal for treatment of combined injury.
Quantitative mathematical modeling of clinical brain metastasis dynamics in non-small cell lung cancer
Authors: Bilous M. , Serdjebi C. , Boyer A. , Tomasini P. , Pouypoudat C. , Barbolosi D. , Barlesi F. , Chomy F. , Benzekry S.
Published: October 2018

Brain metastases (BMs) are associated with poor prognosis in non-small cell lung cancer (NSCLC), but are only visible when large enough. Therapeutic decisions such as whole brain radiation therapy would benefit from patient-specific predictions of radiologically undetectable BMs. Here, we propose a mathematical modeling approach and use it to analyze clinical data of BM from NSCLC.

Primary tumor growth was best described by a gompertzian model for the pre-diagnosis history, followed by a tumor growth inhibition model during treatment. Growth parameters were estimated only from the size at diagnosis and histology, but predicted plausible individual estimates of the tumor age (2.1-5.3 years). Multiple metastatic models were assessed from fitting either literature data of BM probability (n = 183 patients) or longitudinal measurements of visible BMs in two patients. Among the tested models, the one featuring dormancy was best able to describe the data. It predicted latency phases of 4.4 - 5.7 months and onset of BMs 14 - 19 months before diagnosis. This quantitative model paves the way for a computational tool of potential help during therapeutic management.
Crystal structure and Hirshfeld surface analysis of (E)-N′-benzylidene-4-chlorobenzenesulfonohydrazide and of its (E)-4-chloro-N′-(ortho- and para-methylbenzylidene)benzenesulfonohydrazide derivatives
Authors: Salian Akshatha R. , Foro Sabine , Gowda B. Thimme
Published: October 2018

(E)-N′-Benzylidene-4-chlorobenzenesulfonohydrazide, C13H11ClN2O2S, (I), and its ortho- and para-methylsubstituted derivatives, C14H13ClN2O2S, namely (E)-4-chloro-N′-(2-methylbenzylidene)benzenesulfonohydrazide, (II), and (E)-4-chloro-N′-(4-methylbenzylidene)benzenesulfonohydrazide, (III), have been synthesized, characterized spectroscopically and their crystal structures determined to investigate the effect of the substitution site of the benzylidene group on the structural and supramolecular features in these compounds. Compounds (I) and (II) are isotypic while compound (III) is different. All three molecules are bent at the S atom with C—S—N—N torsion angles of −66.0 (3), −66.0 (3) and −58.4 (2)° for (I), (II) and (III), respectively. The hydrazone portions of the molecules, S—N—N=C, are slightly twisted from planarity, with a torsion angle of 166.5 (3)° in (I), 165.4 (3)° in (II) and 157.9 (2)° in (III). The two aromatic rings present in the compounds are inclined to each other by 78.4 (2), 74.8 (2) and 76.9 (1)° in (I), (II) and (III), respectively. In the crystal structure of the parent compound (I), and of the ortho-methyl derivative (II), an N—H...O hydrogen bond links the molecules into chains along [001], which are interconnected by weak intermolecular C—H...O interactions, generating layers lying parallel to the bc plane. In the crystal of the para derivative (III), however, the packing is significantly different. Here molecules are linked by pairs of N—H...O hydrogen bonds, forming inversion dimers with an R
2
2(8) ring motif. The dimers are then linked by C—Cl...π interactions, forming ribbons propagating along [1\overline{1}0]. Hirshfeld surface analyses show that the van der Waals interactions constitute the major contribution to the intermolecular interactions in the crystal structures of all three compounds. The fingerprint plots indicate that the H...H contacts make the largest contributions to the Hirshfeld surfaces.
Crystal structures of three halide salts of L-asparagine: an isostructural series
Authors: Moraes Lygia S. de , Kennedy Alan R. , Logan Charlie R.
Published: October 2018

The structures of three monohydrated halide salt forms of L-asparagine are presented, viz.L-asparaginium chloride monohydrate, C4H9N2O3
+·Cl−·H2O, (I), L-asparaginium bromide monohydrate, C4H9N2O3
+·Br−·H2O, (II), and L-asparaginium iodide monohydrate, C4H9N2O3
+·I−·H2O, (III). These form an isomorphous and isostructural series. The C—C—C—C backbone of the amino acid adopts a gauche conformation in each case [torsion angles for (I), (II) and (III) = −55.4 (2), −55.6 (5) and −58.3 (7)°, respectively]. Each cation features an intramolecular N—H...O hydrogen bond, which closes an S(6) ring. The extended structures feature chains of cations that propagate parallel to the b-axis direction. These are formed by carboxylic acid/amide complimentary O—H...O + N—H...O hydrogen bonds, which generate R
2
2(8) loops. These chains are linked by further hydrogen bonds mediated by the halide ions and water molecules to give a layered structure with cation and anion layers parallel to the ab plane. Compound (III) was refined as an inversion twin.
Diethyl 4-(4-chloro-2-propyl-1H-imidazol-5-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate monohydrate
Authors: Rasheeda Kedila , Samshuddin Seranthimata , Swathi Phadke N. , Alva Vijaya D. P. , Mague Joel T. , Ramli Youssef
Published: October 2018

In the title hydrate, C19H26ClN3O4·H2O, the imidazole ring is nearly perpendicular [dihedral angle = 89.5 (1)°] to the dihydropyridine moiety. The propyl and one of the ethyl groups are disordered over two resolved sets of sites [occupancy factors 0.524 (8):0.476 (8) and 0.640 (16):0.360 (16), respectively]. In the crystal, a three-dimensional network is constructed by O—H...O, N—H...O and N—H...N hydrogen bonds involving both the main molecule and the water molecule of crystallization, as well as C—H...π(ring) interactions.
Development of a functional food bar containing coffee
Authors: Lara Nathália de Souza , de Sousa Maísa Mancini Matioli , Paola de Pádua Gandra Fernanda , de Angelis-Pereira Michel Cardoso , Carneiro João de Deus Souza , Pereira Rosemary Gualberto Fonseca Alvarenga
Published: October 2018

Purpose

The purpose of this paper is to develop a cereal bar supplemented with coffee beverage that has health benefits.

Design/methodology/approach

Six types of cereal bars containing raisins or prunes with different concentrations of coffee were developed. Acceptability tests and physicochemical characterizations were performed by analysis of moisture, ash, protein, lipids, fibres and carbohydrates. Moreover, the levels of phenolic compounds, the fatty acid profile and thein vitroantioxidant activity were evaluated by the DPPH free radical scavenging and iron-chelating activity methods. The bars were assessed using the check-all-that-apply (CATA) methodology. The phenolic compound and antioxidant activity data were evaluated by analysis of variance. Averages were compared by the Scott–Knott test. To verify the characteristics of the food bar per the attributes cited in CATA, main component analysis was performed using the SensoMaker software.

Findings

The concentration of coffee did not affect the centesimal composition values. The highest percentage of scavenging activity of free radicals was observed in the food bar containing raisins, with a maximum concentration of coffee beverage equivalent to 10 mL. These values were higher in cereal bars containing raisins than in bars containing prunes with the same concentrations of coffee. The acceptance sensory test showed good acceptability ratios, ranging from 74.33 to 85.22 among different food bar formulations.

Practical implications

The bar consisting raisins and 100 per cent coffee presented high values of protection against oxidative stress, phenolic content and satisfying acceptability, thereby making it a novel possible alternative as a differentiated product with possible health-beneficial effects.

Social implications

This paper provides a differentiated product, through healthy ingredients, with convenience of purchase, besides having added value and possible health beneficial effects.

Originality/value

The bar consisting of raisins and 100 per cent coffee presented high values of phenolic content and protection against oxidative stress, as well as satisfying acceptability, thereby making it a novel possible alternative as a differentiated product with possible health-beneficial effects.
Digital Korean studies: recent advances and new frontiers
Authors: Cha Javier
Published: October 2018

Purpose

This study aims to reflect on the past and prospects of digital Korean studies.

Design/methodology/approach

Discussion includes the remarkably early adoption of computing in the Korean humanities, the astounding pace in which Korean heritage materials have been digitized, and the challenges of balancing artisanal and laboratory approaches to digital research.

Findings

The main takeaway is to reconsider the widespread tendency in the digital humanities to privilege frequentist analysis and macro-level perspectives.

Practical implications

Cha hopes to discover the future of digital Korean studies in semantic networks, graph databases and anthropological inquiries.

Originality/value

Cha reconsiders existing tendencies in the digital humanities and looks to the future of digital Korean studies.
Variable viscosity effects on third-grade liquid flow in post-treatment analysis of wire coating in the presence of nanoparticles
Authors: Mahanthesh B. , Gireesha B.J. , Archana M. , Hayat Tasawar , Alsaedi Ahmed
Published: October 2018

Purpose

The features of coated wire product are measured by the flow and heat transport occurring in the interior of dies. Therefore, an understanding of characteristics of polymers momentum, heat mass transfer and wall shear stress is of great interest. Enhancement of heat transfer rate is fundamental need of wire coating process. Therefore, this study aims to investigate the effect of suspended nanoparticles in heat and mass transport phenomena of third-grade liquid in post-treatment of wire coating process. Buongiorno model for nanofluid is adopted. Two cases of temperature dependent viscosity are considered.

Design/methodology/approach

The governing equations are modelled with the help of steady-state conservation equations of mass, momentum, energy and nanoparticle concentration. Some appropriate dimensionless variables are introduced. Numerical solutions for the nonlinear problem are developed through Runge–Kutta–Fehlberg technique. The outcome of sundry variables for dimensionless flow, thermal and nanoparticle volume fraction fields are scrutinised through graphical illustrations.

Findings

The study’s numerical results disclose that the force on the total wire surface and shear stress at the surface in case of Reynolds Model dominate Vogel’s Model case. Impact of nanoparticles is constructive for force on the total wire surface and shear stress at the surface. The velocity of the coating material can be enhanced by the non-Newtonian property.

Practical implications

This study may provide useful information to improve the wire coating technology.

Originality/value

Effect of nanoparticles in wire coating analysis by using Brownian motion and thermophoresis slip mechanisms is investigated for the first time. Two different models for variable viscosity are used.
Intersectionality and mixed methods for social context in entrepreneurship
Authors: Dy Angela , Agwunobi Adaku Jennifer
Published: October 2018

Purpose

This conceptual paper has two central aims: to critically analyse the potential of intersectionality theory as a means by which to understand aspects of context in entrepreneurship studies, and advocate for the value of a realist perspective and mixed methods approaches to produce better intersectional research on entrepreneurship. This paper aims to discuss these issues.

Design/methodology/approach

Highlighting context as an emerging topic within entrepreneurship literature, the paper examines how drawing upon notions of intersectionality and positionality can help to explain the social context for entrepreneurial activity and outcomes, particularly in terms of agency and resources.

Findings

The paper complements and extends existing intersectional approaches to entrepreneurship studies by introducing Archer’s critical realist philosophical perspective on agency and Anthias’ positional perspective on resource access, considering the usefulness of realism and mixed methods approaches for such work, and outlining a methodologically informed potential research agenda for the area.

Originality/value

The paper offers a theoretical foundation for researchers to begin systematically exploring social entrepreneurial context by accounting for the effects of overarching intersecting structures such as gender, race, and socio-economic class (amongst others), presents empirical methods through which these social-structural influences, and the degree of their impact, can be identified and analysed, and suggests a philosophically robust means of conceptualising how, in combination with agency, they influence essential aspects of entrepreneurial activity.