bluuebunny/crossref_metadata_2025 huggingface dataset:
Towards reliable named entity recognition in the biomedical domain
Authors: Giorgi John , Bader Gary
Published: January 2019

Motivation: Automatic biomedical named entity recognition (BioNER) is a key task in biomedical information extraction (IE). For some time, state-of-the-art BioNER has been dominated by machine learning methods, particularly conditional random fields (CRFs), with a recent focus on deep learning. However, recent work has suggested that the high performance of CRFs for BioNER may not generalize to corpora other than the one it was trained on. In our analysis, we find that a popular deep learning-based approach to BioNER, known as bidirectional long short-term memory network-conditional random field (BiLSTM-CRF), is correspondingly poor at generalizing - often dramatically overfitting the corpus it was trained on. To address this, we evaluate three modifications of BiLSTM-CRF for BioNER to alleviate overfitting and improve generalization: improved regularization via variational dropout, transfer learning, and multi-task learning.
Results: We measure the effect that each strategy has when training/testing on the same corpus ("in-corpus" performance) and when training on one corpus and evaluating on another ("out-of-corpus" performance), our measure of the models ability to generalize. We found that variational dropout improves out-of-corpus performance by an average of 4.62%, transfer learning by 6.48% and multi-task learning by 8.42%. The maximal increase we identified combines multi-task learning and variational dropout, which boosts out-of-corpus performance by 10.75%. Furthermore, we make available a new open-source tool, called Saber, that implements our best BioNER models.
Availability: Source code for our biomedical IE tool is available at https://github.com/BaderLab/saber. Corpora and other resources used in this study are available at https://github.com/BaderLab/Towards- reliable-BioNER.
The variability of expression of many genes and most functional pathways is observed to increase with age in brain transcriptome data
Authors: Kedlian Veronika R , Donertas Handan Melike , Thornton Janet M
Published: January 2019

Ageing is broadly defined as a time-dependent progressive decline in the functional and physiological integrity of organisms. Previous studies and evolutionary theories of ageing suggest that ageing is not a programmed process but reflects dynamic stochastic events. In this study, we test whether transcriptional noise shows an increase with age, which would be expected from stochastic theories. Using human brain transcriptome dataset, we analysed the heterogeneity in the transcriptome for individual genes and functional pathways, employing different analysis methods and pre-processing steps. We show that unlike expression level changes, changes in heterogeneity are highly dependent on the methodology and the underlying assumptions. Although the particular set of genes that can be characterized as differentially variable is highly dependent on the methods, we observe a consistent increase in heterogeneity at every level, independent of the method. In particular, we demonstrate a weak but reproducible transcriptome-wide shift towards an increase in heterogeneity, with twice as many genes significantly increasing as opposed to decreasing their heterogeneity. Furthermore, this pattern of increasing heterogeneity is not specific but is associated with a wide range of pathways.
ABC transporters alter plant-microbe-parasite interactions in the rhizosphere
Authors: Cox Deborah , Dyer Steven , Weir Ryan , Cheseto Xavier , Sturrock Matthew , Coyne Danny , Torto Baldwyn , Maule Aaron G , Dalzell Johnathan J
Published: January 2019

Plants are master regulators of rhizosphere ecology, secreting a complex mixture of compounds into the soil, collectively termed plant root exudate. Root exudate composition is highly dynamic and functional, mediating interactions between plants and a wide range of beneficial / harmful soil organisms. Exudate composition is under selective pressure to diversify in response to pathogen perception, whilst maintaining interactions with beneficial organisms. However, crop domestication has exerted significant and unintended changes to crop root exudate composition, and we know very little about genotype - phenotype linkages that pertain to root exudates and rhizosphere interactions. Better understanding could enable the modulation of root exudate composition for crop improvement by promoting positive, and impeding negative, interactions. Root expressed transporters modulate exudate composition and could be manipulated towards the rational design of beneficial root exudate profiles. Using Virus Induced Gene silencing (VIGS), we demonstrate that knockdown of two root-expressed ABC transporter genes in tomato cv. Moneymaker, ABC-G33 and ABC-C6, alters the composition of semi-volatile compounds in collected root exudates. Root exudate chemotaxis assays demonstrate that knockdown of each transporter gene triggers the repulsion of economically relevant Meloidogyne and Globodera spp. plant parasitic nematodes, which are attracted to control treatment root exudates. Knockdown of ABC-C6 inhibits egg hatching of Meloidogyne and Globodera spp., relative to controls. Knockdown of ABC-G33 has no impact on egg hatching of Meloidogyne spp. but has a substantial inhibitory impact on egg hatching of G. pallida. ABC-C6 knockdown has no impact on the attraction of the plant pathogen Agrobacterium tumefaciens, or the plant growth promoting Bacillus subtilis, relative to controls. Silencing ABC-G33 induces a statistically significant reduction in attraction of B. subtilis, with no impact on attraction of A. tumefaciens. ABC-C6 represents a promising target for breeding or biotechnology intervention strategies as gene knockdown (-64.9%) leads to the repulsion of economically important plant parasites and retains attraction of the beneficial rhizobacterium B. subtilis. This study exposes the link between ABC transporters, root exudate composition, and ex planta interactions with agriculturally and economically relevant rhizosphere organisms, paving the way for an entirely new approach to rhizosphere engineering and crop protection.
The Vibrio cholerae MARTX toxin simultaneously induces actin collapse while silencing the inflammatory response to cytoskeletal damage
Authors: Woida Patrick J. , Satchell Karla J. F.
Published: January 2019

Abstract

Multifunctional autoprocessing repeats-in-toxin (MARTX) toxins are pore-forming toxins that translocate multiple functionally independent effector domains into a target eukaryotic cell. Vibrio cholerae colonizes intestinal epithelial cells (IECs) and utilizes a MARTX toxin with three effector domains — an actin cross-linking domain (ACD), a Rho inactivation domain (RID), and an α/β hydrolase domain (ABH) — to suppress innate immunity and enhance colonization. We investigated whether these multiple catalytic enzymes delivered from a single toxin function in a coordinated manner to regulate intestinal innate immunity. Using cultured IECs, we demonstrate that ACD-induced cytoskeletal collapse activated ERK, p38, and JNK mitogen-activated protein kinase (MAPK) signaling to elicit a robust proinflammatory response characterized by production of interleukin-8 (IL-8) and expression of CXCL8, TNF, and other proinflammatory genes. However, RID and ABH, which are naturally delivered along with ACD, blocked MAPK activation via Rac1 and thus prevented the ACD-induced inflammation. RID also abolished IL-8 secretion induced by heat-killed bacteria, tumor necrosis factor, and latrunculin A. Thus, MARTX toxins utilize enzymatic multifunctionality to silence the host response to bacterial factors and to the damage it causes. Further, these data show how V. cholerae MARTX toxin suppresses intestinal inflammation and contributes to cholera being classically defined as non-inflammatory diarrheal disease.
Temporal gating of synaptic competition in the lateral amygdala by cannabinoid receptor modulation of the thalamic input
Authors: Drumond Ana , Madeira Natália , Fonseca Rosalina
Published: January 2019

The acquisition of fear memories involves plasticity of the thalamic and cortical pathways to the lateral amygdala (LA). The maintenance of synaptic plasticity requires the interplay between input-specific synaptic tags and the allocation of plasticity-related proteins (PRPs). Based on this interplay, weakly activated synapses can express long-lasting synaptic plasticity by cooperation with strongly activated ones. Increasing the number of activated synapses can shift cooperation to competition. Synaptic cooperation and competition can determine whether two events, separated in time, are linked or selected. The rules that determine whether synapses cooperate or compete are unknown. We found that synaptic cooperation and competition, in the LA, are determined by the temporal sequence of cortical and thalamic stimulation and that the strength of the synaptic tag is modulated by the endocannabinoid signalling. This modulation is particularly effective in thalamic synapses, suggesting a critical role of endocannabinoids in restricting thalamic plasticity. Also, we found that PRPs availability is modulated by the action-potential firing of neurons, shifting competition to cooperation. Our data present the first evidence that pre-synaptic modulation of synaptic activation, by the cannabinoid signalling, function as a temporal gating mechanism limiting synaptic cooperation and competition.
Folding landscape of a parallel G-quadruplex
Authors: Gray Robert D , Trent John O , Arumugam Sengodagounder , Chaires Jonathan
Published: January 2019

Circular dichroism and stopped-flow UV spectroscopies were used to investigate the thermodynamic stability and the folding pathway of d(TGAG3TG3TAG3TG3TA2) at 25C in solutions containing 25 mM KCl. Under these conditions the oligonucleotide adopts a thermally stable, all-parallel G-quadruplex topography containing three stacked quartets. K+-induced folding shows three resolved relaxation times, each with distinctive spectral changes. Folding is complete within 200 s. These data indicate a folding pathway that involves at least two populated intermediates, one of which seems to be an antiparallel structure that rearranges to the final all-parallel conformation. Molecular dynamics reveals a stereochemically plausible folding pathway that does not involve complete unfolding of the intermediate. The rate of unfolding was determined using complementary DNA to trap transiently unfolded states to form a stable duplex. As assessed by 1D-1H NMR and fluorescence spectroscopy, unfolding is extremely slow with only one observable rate-limiting relaxation time.
Antarctica's wilderness has declined to the exclusion of biodiversity
Authors: Leihy Rachel I. , Coetzee Bernard W.T. , Morgan Fraser , Raymond Ben , Shaw Justine D. , Terauds Aleks , Chown Steven L.
Published: January 2019

Recent assessments of the biodiversity value of Earth's dwindling wilderness areas have emphasized the whole of Antarctica as a crucial wilderness in need of urgent protection. Whole-of-continent designations for Antarctic conservation remain controversial, however, because of widespread human impacts and frequently used provisions in Antarctic law for the designation of specially protected areas to conserve wilderness values, species and ecosystems. Here we investigate the extent to which Antarctica's wilderness encompasses its biodiversity. We assembled a comprehensive record of human activity on the continent (~ 2.7 million localities) and used it to identify unvisited areas ≥ 10 000 km2 (i.e. Antarctica's wilderness areas) and their representation of biodiversity. We show that, at best, 7 770 000 km2 of wilderness remains, covering 56.9% of the continent's surface area, however it captures few important biodiversity features. Important Bird Areas, ice-free Antarctic Conservation Biogeographic Regions crucial for biodiversity and areas with verified biodiversity records are largely excluded. Our results demonstrate that Antarcticas wilderness has already declined to the exclusion of much of its biodiversity. But that on a continent set aside as a natural reserve, increased regulation of human activity and urgent expansion of the Antarctic specially protected area network could feasibly reverse this trend.
Attentional amplification of neural codes for number independent of other quantities along the dorsal visual stream
Authors: Castaldi Elisa , Piazza Manuela , Dehaene Stanislas , Vignaud Alexandre , Eger Evelyn
Published: January 2019

Humans and other animals base important decisions on estimates of number, and intraparietal cortex is thought to provide a crucial substrate of this ability. However, it remains debated whether an independent neuronal processing mechanism underlies this 'number sense', or whether number is instead judged indirectly on the basis of other quantitative features. We performed high-resolution 7 Tesla fMRI while adult human volunteers attended either to the numerosity or to an orthogonal dimension (average item size) of visual dot arrays. Numerosity explained a significant amount of variance in activation patterns, above and beyond non-numerical dimensions. Its representation was progressively enhanced along the dorsal visual pathway and was selectively amplified by attention when task relevant. These results reveal a dedicated extraction mechanism for numerosity that operates independently of other quantitative dimensions of the stimuli, and suggest that later stages along the dorsal stream are most important for the explicit manipulation of numerical quantity.
Placental effects on maternal brain revealed by disrupted placental gene expression in mouse hybrids
Authors: Arévalo Lena , Campbell Polly
Published: January 2019

The mammalian placenta is both the physical interface between mother and fetus, and the source of endocrine signals that target the maternal hypothalamus, priming females for parturition, lactation and motherhood. Despite the importance of this connection, the effects of altered placental signaling on the maternal brain are understudied. Here, we show that placental dysfunction alters gene expression in the maternal brain, with the potential to affect maternal behavior. Using a cross between the house mouse and the Algerian mouse in which hybrid placental development is abnormal, we sequenced late gestation placental and maternal medial preoptic area transcriptomes and quantified differential expression and placenta-maternal brain co-expression between normal and hybrid pregnancies. The expression ofFmn1, Drd3, Caln1andCtsrwas significantly altered in the brains of females exposed to hybrid placentas. Most strikingly, expression patterns of placenta-specific gene families andDrd3in the brains of house mouse females carrying hybrid litters matched those of female Algerian mice, the paternal species in the cross. Our results indicate that the paternally-derived placental genome can influence the expression of maternal-fetal communication genes, including placental hormones, suggesting an effect of the offspring’s father on the mother’s brain.
Mechanical and thermodynamic properties of Aβ42, Aβ40 and α-synuclein fibrils: A coarse-grained method to complement experimental studies
Authors: Poma Adolfo , Vargas Guzman Horacio Andres , Li Mai Suan , Theodorakis Panagiotis
Published: January 2019

We perform molecular dynamics simulation on several relevant biological fibrils associated with neurodegenerative diseases such as Aβ40, Aβ42, and the β-synuclein systems to obtain a molecular understanding and interpretation of nanomechanical characterization experiments. The computational method is versatile and addresses a new subarea within the mechanical characterization of heterogeneous soft materials. We investigate both the elastic and thermodynamic properties of the biological fibrils in order to substantiate experimental nanomechanical characterization techniques that are quickly developing and reaching dynamic imaging with video rate capabilities. The computational method qualitatively reproduces results of experiments with biological fibrils, validating its use in extrapolation to macroscopic material properties. Our computational techniques can be used for the co-design of new experiments aiming to unveil nanomechanical properties of biological fibrils from a molecular understanding point of view. Our approach allows a comparison of diverse elastic properties of the latter fibrils, which enables the detailed analysis of the mechanical response at the molecular level. For these systems, the simulation approach indicates qualitative agreement with the experimental estimations of the elastic moduli for three different types of deformation, i.e. tensile (YL), shear (S), and indentation (YT ). From our analysis, we find a significant elastic anisotropy between axial and transverse directions (i.e. YT>YL) for all systems. Interestingly, our results indicate a higher mechanostability in the case of Aβ42 fibrils than in the case of β40, suggesting a significant correlation between mechanical stability and aggregation propensity (rate) in amyloid systems, that is, the higher the mechanical stability the faster the fibril formation. Finally, we find that α-synuclein fibrils are thermally less stable than β-amyloid fibrils. We anticipate that our molecular-level analysis of the mechanical response under different deformation conditions for the range of fibrils considered here will provide significant insights for the experimental observations.
The biofilm matrix scaffold of Pseudomonas species contains non-canonically base paired extracellular DNA and RNA
Authors: Seviour Thomas , Winnerdy Fernaldo Richtia , Wong Lan Li , Shi Xiangyan , Mugunthan Sudarsan , Castaing Remi , Adav Sunil S , Kohli Gurjeet Singh , Shewan Heather M , Stokes Jason R , Rice Scott A. , Phan Anh Tuân , Kjelleberg Staffan
Published: January 2019

While extracellular DNA (eDNA) is recognized as a critical biofilm matrix component, it is not understood how it contributes to biofilm function. Here we isolate eDNA from Pseudomonas biofilms using ionic liquids, and discover that its key biophysical signatures, i.e. fluid viscoelasticity, nucleic acid conformation, and temperature and pH dependencies of gel to solution transitions, are maintained. Solid-state analysis of isolated eDNA, as a proxy for eDNA structure in biofilms, revealed non-canonical Hoogsteen base pairs, triads or tetrads involving guanine and thymine or uracil. These were less abundant in chromosomal DNA and undetected as eDNA underwent gel-sol transition. Purine-rich RNA was present in the eDNA network, which potentially enables eDNA to be the main cross-linking exopolymer in the matrix through non-canonical nucleobase interactions. Our study suggests that Pseudomonas assemble extracellular DNA and RNA into a network with viscoelastic properties, which underpin their persistence and spreading, and may aid the development of more effective controls for biofilm-associated infections.
Super-resolving light fields in microscopy: depth from disparity
Authors: Sims Ruth R. , Abdul Rehman Sohaib , Lenz Martin O. , Mureşan Leila , O'Holleran Kevin
Published: January 2019

Single molecule localisation microscopy (SMLM) has opened a new window for imaging fluorescently labelled biological specimens. Common 3D SMLM techniques enable data collection across an axial range of 1 - 5μm with high precision. Despite the success of 3D single molecule imaging there is a real need to image larger volumes. Here we demonstrate, through simulation and experiment, the potential of Single Molecule Light Field Microscopy (SMLFM) for extended depth-of-field super-resolution imaging, extracting 3D point source position by measuring the disparity between localizations of a point emitter in multiple perspective views.
Splicing buffers suboptimal codon usage in human cells
Authors: Mordstein Christine , Savisaar Rosina , Young Robert S , Bazile Jeanne , Talmane Lana , Luft Juliet , Liss Michael , Taylor Martin S , Hurst Laurence D , Kudla Grzegorz
Published: January 2019

Although multiple studies have addressed the effects of codon usage on gene expression, such studies were typically performed in unspliced model genes. In the human genome, most genes undergo splicing and patterns of codon usage are splicing-dependent: guanine and cytosine (GC) content is highest within single-exon genes and within first exons of multi-exon genes. Intrigued by this observation, we measured the effects of splicing on expression in a panel of synonymous variants of GFP and mKate2 reporter genes that varied in nucleotide composition. We found that splicing promotes the expression of adenine and thymine (AT)-rich variants by increasing their steady-state protein and mRNA levels, in part through promoting cytoplasmic localization of mRNA. Splicing had little or no effect on the expression of GC-rich variants. In the absence of splicing, high GC content at the 5' end, but not at the 3' end of the coding sequence positively correlated with expression. Among endogenous human protein-coding transcripts, GC content has a more positive effect on various expression measures of unspliced, relative to spliced mRNAs. We propose that splicing promotes the expression of AT-rich genes, leading to selective pressure for the retention of introns in the human genome.
C99 selectively accumulates in vulnerable neurons in Alzheimer’s disease
Authors: Pulina Maria V. , Hopkins Maya , Haroutunian Vahram , Greengard Paul , Bustos Victor
Published: January 2019

Introduction

The levels and distribution of amyloid deposits in the brain does not correlate well with Alzheimer’s disease (AD) progression. Therefore, it is likely that Amyloid-precursor-protein proteolytic fragments other than beta-amyloid contribute to the onset of AD.

Methods

We developed a sensitive assay adapted to the detection of C99, the direct precursor of beta-amyloid. Three postmortem groups were studied: control with normal and stable cognition; subjects with moderate AD, and individuals with severe AD. The amount of C99 and beta-amyloid was quantified and correlated with the severity of AD.

Results

C99 accumulates in vulnerable neurons, and its levels correlate with the degree of cognitive impairment in patients suffering from AD. In contrast, beta-amyloid levels are increased in both vulnerable and resistant brain areas.

Discussion

These results raise the possibility that C99, rather than beta-amyloid plaques, is responsible for the death of nerve cells in Alzheimer’s disease.
Genetic instability as a driver for immune surveillance
Authors: Aguade Guim , Sole Ricard
Published: January 2019

Genetic instability is known to relate with carcinogenesis by providing tumors with a mechanism for fast adaptation. However, mounting evidence also indicates causal relation between genetic instability and improved cancer prognosis resulting from efficient immune response. Highly unstable tumors seem to accumulate mutational burdens that result in dynamical landscapes of neoantigen production, eventually inducing acute immune recognition. How are tumor instability and enhanced immune response related? An important step towards future developments involving combined therapies would benefit from unraveling this connection. In this paper we present a minimal mathematical model to describe the ecological interactions that couple tumor adaptation and immune recognition while making use of available clinical estimates of relevant parameters. The possible evolutionary trade-offs associated to both cancer replication and T cell response are analysed, indicating that cancer-clearance states become attainable when both mutational load and immune migration are enhanced. Furthermore, the model predicts the presence of well-defined transitions towards tumor control and eradication after increases in genetic instability consistent with available data of tumor control after Mismatch Repair knockout.
Gibbs Free Energy, a thermodynamic measure of protein-protein interactions, correlates with neurologic disability
Authors: Keegan Michael , Siegelmann Hava T , Rietman Edward A , Klement Giannola Lakka
Published: January 2019

Background: Modern network science has been used to reveal new and often fundamental aspects of brain network organization in physiological as well as pathological conditions. As a consequence, these discoveries, which relate to network hierarchy, hubs and network interactions, begun to change the paradigms of neurodegenerative disorders. We therefore explored the use of thermodynamics for protein-protein network interactions in Alzheimer disease (AD), Parkinson disease (PD), multiple sclerosis (MS), traumatic brain injury and epilepsy.
Methods: To assess the validity of using network interactions in neurological disease, we investigated the relationship between network thermodynamics and molecular systems biology for these neurological disorders. In order to uncover whether there was a correlation between network organization and biological outcomes, we used publicly available RNA transcription data from individual patients with these neurological conditions, and correlated these molecular profiles with their respective individual disability scores.
Results: We found a linear correlation (Pearson correlation of -0.828) between disease disability (a clinically validated measurement of a person's functional status), and Gibbs free energy (a thermodynamic measure of protein-protein interactions). In other words, we found an inverse relationship between disease entropy and thermodynamic energy.
Interpretation: Because a larger degree of disability correlated with a larger negative drop in Gibbs free energy in a linear, disability-dependent fashion, it could be presumed that the progression of neuropathology such as is seen in Alzheimer Disease, could potentially be prevented by therapeutically correcting the changes Gibbs free energy.
Paternally-acting canonical RNA-directed DNA methylation pathway genes sensitize Arabidopsis endosperm to paternal genome dosage
Authors: Satyaki P. R. V. , Gehring Mary
Published: January 2019

Seed development is sensitive to parental dosage, with excess maternal or paternal genomes creating reciprocal phenotypes. Paternal genomic excess frequently results in extensive endosperm proliferation without cellularization and seed abortion. We previously showed that loss of the RNA Pol IV genenrpd1in tetraploid fathers represses seed abortion in paternal excess crosses. Here we show genetically that RNA-directed DNA methylation (RdDM) pathway activity in the paternal parent is sufficient to determine the viability of paternal excess seeds. We compared transcriptomes, DNA methylation, and small RNAs from endosperm of balanced crosses (diploid × diploid) and lethal (diploid × tetraploid) and viable paternal excess (diploid × tetraploidnrpd1). Endosperm from both lethal and viable paternal excess seeds share widespread transcriptional and DNA methylation changes at genes and TEs. Interploidy seed abortion is thus unlikely to be caused by either transposable element or imprinted gene mis-regulation, and its repression by loss of paternal RdDM is associated with only modest gene expression changes. Finally, using allele-specific transcription data, we present evidence for a transcriptional buffering system that increases expression of maternal alleles and represses paternal alleles in response to excess paternal genomic dosage. These findings prompt reconsideration of models for dosage sensitivity in endosperm.
Acis-carotene derived apocarotenoid regulates etioplast and chloroplast development
Authors: Cazzonelli Christopher I , Hou Xin , Alagoz Yagiz , Rivers John , Dhami Namraj , Lee Jiwon , Shashikanth Marri , Pogson Barry J
Published: January 2019

Carotenoids are core plastid components, yet a regulatory function during plastid biogenesis remains enigmatic. A unique carotenoid biosynthesis mutant,carotenoid chloroplast regulation 2(ccr2), that has no prolamellar body (PLB) and normal PROTOCHLOROPHYLLIDE OXIDOREDUCTASE (POR) levels, was used to demonstrate a regulatory function for carotenoids under varied dark-light regimes. A forward genetics approach revealed how an epistatic interaction between a(-carotene isomerasemutant (ziso-155) andccr2blocked the biosynthesis of specificcis-carotenes and restored PLB formation in etioplasts. We attributed this to a novel apocarotenoid signal, as chemical inhibition of carotenoid cleavage dioxygenase activity restored PLB formation inccr2etioplasts during skotomorphogenesis. The apocarotenoid acted in parallel to the transcriptional repressor of photomorphogenesis, DEETIOLATED1 (DET1), to post-transcriptionally regulate PROTOCHLOROPHYLLIDE OXIDOREDUCTASE (POR), PHYTOCHROME INTERACTING FACTOR3 (PIF3) and ELONGATED HYPOCOTYL5 (HY5) protein levels. The apocarotenoid signal anddet1complemented each other to restore POR levels and PLB formation, thereby controlling plastid development.

One-sentence summary

Carotenoids are not just required as core components for plastid biogenesis, they can be cleaved into an apocarotenoid signal that regulates etioplast and chloroplast development during extended periods of darkness.
Cryopreservation of Paramecium bursaria Chlorella Virus-1 during an active infection cycle of its host
Authors: Coy Samantha R. , Alsante Alyssa N. , Van Etten James L. , Wilhelm Steven W.
Published: January 2019

Best practices in laboratory culture management often include cryopreservation of microbiota, but this can be challenging with some virus particles. By preserving viral isolates researchers can mitigate genetic drift and laboratory-induced selection, thereby maintaining genetically consistent strains between experiments. To this end, we developed a method to cryopreserve the model, green-alga infecting virus,Paramecium bursaria Chlorella virus 1(PBCV-1). We explored cryotolerance of the infectivity of this virus particle, whereby freezing without cryoprotectants was found to maintain the highest infectivity (~2.5%). We then assessed the cryopreservation potential of PBCV-1 during an active infection cycle in itsChlorella variabilisNC64A host, and found that virus survivorship was highest (69.5 ± 16.5 %) when the infected host is cryopreserved during mid-late stages of infection (i.e., coinciding with virion assembly). The most optimal condition for cryopreservation was observed at 240 minutes post-infection. Overall, utilizing the cell as a vehicle for viral cryopreservation resulted in 24.9 – 30.1 fold increases in PBCV-1 survival based on 95% confidence intervals of frozen virus particles and virus cryopreserved at 240 minutes post-infection. Given that cryoprotectants are often naturally produced by psychrophilic organisms, we suspect that cryopreservation of infected hosts may be a reliable mechanism for virus persistence in non-growth permitting circumstances in the environment, such as ancient permafrosts.
Solvent-mediated structural transformations of copper(II) coordination polymers induced by different short-chain alcohols
Authors: Ming Mei , Shi Jun
Published: January 2019

A three-dimensional copper(II) coordination polymer (CP), {Cu(L-F)(N3)}
n
(1), was synthesized by reacting Cu(NO3)2 with 5-fluoronicotinic acid (HL-F) and NaN3 in a water medium. Complex (1) shows a 3D network, in which the 1D [Cu2(COO)N3]
n
chains are interconnected via L-F ligands. By immersing (1) into different short-chain alcohols (CH3OH, C2H5OH and HOC2H4OH), three different CPs were isolated, including {Cu3(L-F)4(N3)2(CH3OH)2}
n
(2), {Cu3(L-F)4(N3)2(C2H5OH)2}
n
(3) and {Cu2.5(L-F)3(N3)2(HOC2H4OH)0.5}
n
(4). CPs (2) and (3) display a similar structure, in which trinuclear subunit [Cu3(COO)2(N3)2(solvent)2] is generated. Furthermore, such entities are interconnected via L-F ligands to give rise to a 3D network. As for (4), there are trinuclear [Cu3(COO)2(N3)2] and binuclear [Cu2(COO)N3] units, which are interconnected by L-F ligands to generate a 3D network. Notably, in (2) and (3), the coordination modes of CH3OH and C2H5OH solvents are monodentate; whereas for (4), the HOC2H4OH solvent adopts a bridging mode to link two Cu atoms. Of further interest, these processes are solvent-mediated structural transformations, with obvious colour changes in the crystals. Structural changes and mechanisms of transformation are discussed in detail.
Tantalum isocyanide complexes: TaI(CNDipp)6 (Dipp is 2,6-diisopropylphenyl) and ionic [Ta(CNDipp)7][Ta(CNDipp)6], a formal disproportionation product of the 17-electron Ta0 metalloradical Ta(CNDipp)6
Authors: Brennessel William W. , Romanenkov Alexander , Young Victor G. , Ellis John E.
Published: January 2019

Treatment of tetraethylammonium hexacarbonyltantalate, [Et4N][Ta(CO)6], with 1.1 equivalents of molecular iodine (I2) in tetrahydrofuran (THF) at 200 K, followed by the addition of 6.0 equivalents of 2,6-diisopropylphenyl isocyanide (CNDipp) and slow warming to 293 K over a 24 h period gave the tantalum(I) iodide derivative hexakis(2,6-diisopropylphenyl isocyanide-κC)iodidotantalum(I), [TaI(C13H17N)6] or TaI(CNDipp)6, 1. Recrystallization of this substance from pentane provided deep-red nearly black parallelepipeds of the product, which was characterized by single-crystal X-ray diffraction. Addition of 1 in THF at 200 K to a suspension of an excess (5.8 equivalents) of caesium graphite (CsC8), followed by warming, filtration, and solvent removal, afforded a dark-green oily solid of unknown composition, from which several red–brown rhombohedral plates of the ditantalum salt heptakis(2,6-diisopropylphenyl isocyanide-κC)tantalum hexakis(2,6-diisopropylphenyl isocyanide-κC)tantalate, [Ta(C13H17N)7][Ta(C13H17N)6] or [Ta(CNDipp)7][Ta(CNDipp)6], 2, were harvested. Salt 2 is a unique substance, as it is the only known example of a salt containing a homoleptic cation, [MLx
]+, and a homoleptic anion, [MLy
]−, with the same transition metal and π-acceptor ligand L. In solution, 2 undergoes full comproportionation to afford the recently reported 17-electron paramagnetic zerovalent tantalum complex Ta(CNDipp)6, the only known isolable TaL
6 complex of Ta0.
Structures of the antibody 64M-5 Fab and its complex with dT(6–4)T indicate induced-fit and high-affinity mechanisms
Authors: Yokoyama Hideshi , Mizutani Ryuta , Noguchi Shuji , Hayashida Naoki
Published: January 2019

DNA photoproducts with (6–4) pyrimidine–pyrimidone adducts produced by ultraviolet light are mutagenic and carcinogenic. The crystal structures of the anti-(6–4) photoproduct antibody 64M-5 Fab and of its complex with dT(6–4)T were determined at 2.5 and 2.0 Å resolution, respectively. A comparison between the dT(6–4)T-liganded and unliganded structures indicates that the side chain of His93L is greatly rotated and shifted on binding to dT(6–4)T, leading to the formation of an electrostatic interaction with the phosphate moiety of dT(6–4)T, which shows a remarkable induced fit. Based on a comparison of the dT(6–4)T-liganded structures of the 64M-5 and 64M-2 Fabs, the electrostatic interaction between the side chain of His93L in 64M-5 and the phosphate moiety of dT(6–4)T is lost for Leu93L in 64M-2, while Arg90L in 64M-5 instead of Gln90L in 64M-2 stabilizes the conformation of complementarity-determining region (CDR) L3. These differences contribute to the higher affinity of 64M-5 for dT(6–4)T compared with that of 64M-2.
A revisited version of the apo structure of the ligand-binding domain of the human nuclear receptor retinoic X receptor α
Authors: Eberhardt Jérôme , McEwen Alastair G. , Bourguet William , Moras Dino , Dejaegere Annick
Published: January 2019

The retinoic X receptor (RXR) plays a crucial role in the superfamily of nuclear receptors (NRs) by acting as an obligatory partner of several nuclear receptors; its role as a transcription factor is thus critical in many signalling pathways, such as metabolism, cell development, differentiation and cellular death. The first published structure of the apo ligand-binding domain (LBD) of RXRα, which is still used as a reference today, contained inaccuracies. In the present work, these inaccuracies were corrected using modern crystallographic tools. The most important correction concerns the presence of a π-bulge in helix H7, which was originally built as a regular α-helix. The presence of several CHAPS molecules, which are visible for the first time in the electron-density map and which stabilize the H1–H3 loop, which contains helix H2, are also revealed. The apo RXR structure has played an essential role in deciphering the molecular mode of action of NR ligands and is still used in numerous biophysical studies. This refined structure should be used preferentially in the future in interpreting experiments as well as for modelling and structural dynamics studies of the apo RXRα LBD.
Titration of ionizable groups in proteins using multiple neutron data sets from a single crystal: application to the small GTPase Ras
Authors: Knihtila Ryan , Volmar Alicia Y. , Meilleur Flora , Mattos Carla
Published: January 2019

Neutron protein crystallography (NPC) reveals the three-dimensional structures of proteins, including the positions of H atoms. The technique is particularly suited to elucidate ambiguous catalytic steps in complex biochemical reactions. While NPC uniquely complements biochemical assays and X-ray structural analyses by revealing the protonation states of ionizable groups at and around the active site of enzymes, the technique suffers from a major drawback: large single crystals must be grown to compensate for the relatively low flux of neutron beams. However, in addition to revealing the positions of hydrogens involved in enzyme catalysis, NPC has the advantage over X-ray crystallography that the crystals do not suffer radiation damage. The lack of radiation damage can be exploited to conduct in crystallo parametric studies. Here, the use of a single crystal of the small GTPase Ras to collect three neutron data sets at pD 8.4, 9.0 and 9.4 is reported, enabling an in crystallo titration study using NPC. In addition to revealing the behavior of titratable groups in the active site, the data sets will allow the analysis of allosteric water-mediated communication networks across the molecule, particularly regarding Cys118 and three tyrosine residues central to these networks, Tyr32, Tyr96 and Tyr137, with pK
a values expected to be in the range sampled in our experiments.
Crystallization and X-ray analysis of monodisperse human properdin
Authors: Pedersen Dennis Vestergaard , Revel Margot , Gadeberg Trine Amalie Fogh , Andersen Gregers Rom
Published: January 2019

The 54 kDa protein properdin, also known as factor P (FP), plays a major role in the complement system through the stabilization of the alternative pathway convertases. FP circulates in the blood as cyclic dimers, trimers and tetramers, and this heterogeneity challenges detailed structural insight into the mechanism of convertase stabilization by FP. Here, the generation of an intact FP monomer and a variant monomer with the third thrombospondin repeat liberated is described. Both FP monomers were excised from recombinant full-length FP containing internal cleavage sites for TEV protease. These FP monomers could be crystallized, and complete data sets extending to 2.8 Å resolution for the intact FP monomer and to 3.5 Å resolution for the truncated variant were collected. The principle of specific monomer excision and domain removal by the insertion of a protease cleavage site may be broadly applicable to structural studies of oligomeric, flexible and modular proteins.
Dynamization of bankruptcy models via indicator variables
Authors: Nyitrai Tamás
Published: January 2019

Purpose

The purpose of this paper is to enhance the predictive power of bankruptcy prediction models by taking the past values of firms’ financial ratios as benchmark. For this purpose, the paper proposes an indicator variable expressing the time trends of financial ratios.

Design/methodology/approach

The proposed measure uses the minimum and the maximum of financial ratios from the previous period as benchmarks in order to give a more complete picture about the present financial performance of firms. The most popular classification methods of bankruptcy prediction were employed: discriminant analysis, logistic regression, decision trees. Sample specific results and conclusions were avoided by applying tenfold stratified cross-validation.

Findings

The empirical results suggest that the proposed measure can increase the predictive performance of bankruptcy prediction models compared to models based solely on static financial ratios. The results gave evidence for the fact that the firms’ past financial performance is a useful benchmark for evaluating the risk of future insolvency.

Originality/value

The proposed concept is completely new to the literature and practice of bankruptcy prediction. Similar concept has not been published to date. The suggested dynamization approach has three important advantages. It is easy to compute from time series of financial ratios. It is applicable within any classifier irrespective of its mathematical background. The performance of models can be enhanced without the necessity of giving up the interpretability of bankruptcy models, so the proposed measure may play very important role in the practice of credit scoring modeling as well.
The limits and promises of embeddedness as a strategy for social value creation
Authors: Lashitew Addisu A. , van Tulder Rob
Published: January 2019

Purpose

Multinational enterprises (MNEs) attempting to create social value in base of the pyramid (BoP) economies are encumbered by unique market and institutional barriers. To overcome these challenges, BoP scholars have advocated the strategy of using embeddedness as a replacement for inefficient formal institutions. Reliance on informal social ties for coordinating market exchange, however, leads to costly investments, exposure to opportunism and the creation of nontransferable capabilities. This paper aims to investigate these issues.

Design/methodology/approach

The authors argue that embeddedness should be used as an intermediate step toward developing more enduring formal institutions rather than as a replacement for them.

Findings

The authors put forward the notion of proto-institutions as a useful concept for exploring how MNEs can engage in co-designing efficient and inclusive institutional forms aimed at engendering long-term social value creation.

Originality/value

The authors identify three institutional fields wherein MNEs can leverage social embeddedness to develop proto-institutions that are potentially transferable to become formal institutions. First, MNEs can build governance institutions that can enhance coordination among local actors. Second, MNEs can experiment with small-scale change and adaptation of market institutions that reduce transaction costs and facilitate market exchanges. For example, improved institutional practices in value chain governance can boost business performance while also improving the livelihoods of supply chain partners. Finally, the authors discuss the potential for developing favorable socio-cultural institutions by introducing new principles of organizing or educational practices.
Future-proofing placements
Authors: Fowlie Julie , Forder Clare
Published: January 2019

Purpose

The purpose of this paper is to present a case study centred on steps taken at a Business School in a UK university, to improve local work placement provision, respond to student demand and engage more productively with local businesses. It is situated against renewed focus on universities’ engagement with local economies and the graduate labour market context as demonstrated by the government’s Industrial Strategy (BEIS, 2017) and the OfS (2018) business plan. It aims to emphasise how moving the focus back from graduates to placement students could offer a useful collaborative opportunity for local businesses to articulate what they want from future employees.

Design/methodology/approach

The paper follows a mixed methods approach, drawing upon a case study on a new intervention piloted in the Business School as well as qualitative research gathered from questionnaires and interviews with students. Responses to questionnaires and interviews were analysed thematically in the Grounded Theory (Glaser and Strauss, 1967) tradition.

Findings

The paper highlights the lack of literature on local placements and also demonstrates findings which echo existing research on typical barriers and drivers to placements in general. It offers original outcomes such as how for some students local placements offer a convenience value but for others they are part of committing to living and working locally after graduation.

Research limitations/implications

The small-scale nature of the study means that only indicative findings are presented. Further research is necessary for a more detailed examination of its implications.

Practical implications

Recommendations are made for a systematic approach to developing, or establishing for the first time, university–employer relationships in order to future-proof local placement opportunities.

Originality/value

The paper fills a gap in the literature on local placements and also provides a fresh approach to how universities and employers might work together to identify local skills gaps and increase the provision of local placements. It also offers ways in students’ often negatively framed reasons for not undertaking a placement can be mitigated through engaging with the local context.
Modified algebraic model of laminar-turbulent transition for internal flows
Authors: Nering Konrad , Rup Kazimierz
Published: January 2019

Purpose

For internal flows with small values of the Reynolds number, there is often at a considerable distance from the pipe inlet cross-section a change of the flow form from laminar to turbulent. To describe this phenomenon of laminar-turbulent transition in the pipe, also parallel-plate channel flow, a modified algebraic intermittency model was used. The original model for bypass transition developed by S. Kubacki and E. Dick was designed for simulating bypass transition in turbomachinery.

Design/methodology/approach

A modification of mentioned model was proposed. Modified model is suitable for simulating internal flows in pipes and parallel-plate channels. Implementation of the modified model was made using the OpenFOAM framework. Values of several constants of the original model were modified.

Findings

For selected Reynolds numbers and turbulence intensities (Tu), localization of laminar breakdown and fully turbulent flow was presented. Results obtained in this work were compared with corresponding experimental results available in the literature. It is particularly worth noting that asymptotic values of wall shear stress in flow channels and asymptotic values of axis velocity obtained during simulations are similar to related experimental and theoretical results.

Originality/value

The modified model allows precision numerical simulation in the area of transitional flow between laminar, intermittent and turbulent flows in pipes and parallel-plate channels. Proposed modified algebraic intermittency model presented in this work is described by a set of two additional partial differential equations corresponding with k-omega turbulence model presented by Wilcox (Wilcox, 2006).