bluuebunny/crossref_metadata_2025 huggingface dataset:
Microfabrication of liver and heart tissues for drug development
Authors: Brown Grace E. , Khetani Salman R.
Published: May 2018

Drug-induced liver- and cardiotoxicity remain among the leading causes of preclinical and clinical drug attrition, marketplace drug withdrawals and black-box warnings on marketed drugs. Unfortunately, animal testing has proven to be insufficient for accurately predicting drug-induced liver- and cardiotoxicity across many drug classes, likely due to significant differences in tissue functions across species. Thus, the field of
in vitro
human tissue engineering has gained increasing importance over the last 10 years. Technologies such as protein micropatterning, microfluidics, three-dimensional scaffolds and bioprinting have revolutionized
in vitro
platforms as well as increased the long-term phenotypic stability of both primary cells and stem cell-derived differentiated cells. Here, we discuss advances in engineering approaches for constructing
in vitro
human liver and heart models with utility for drug development. Design features and validation data of representative models are presented to highlight major trends followed by the discussion of pending issues. Overall, bioengineered liver and heart models have significantly advanced our understanding of organ function and injury, which will prove useful for mitigating the risk of drug-induced organ toxicity to human patients, reducing animal usage for preclinical drug testing, aiding in the discovery of novel therapeutics against human diseases, and ultimately for applications in regenerative medicine.

This article is part of the theme issue ‘Designer human tissue: coming to a lab near you’.
Impedance-based cellular assays for regenerative medicine
Authors: Gamal W. , Wu H. , Underwood I. , Jia J. , Smith S. , Bagnaninchi P. O.
Published: May 2018

Therapies based on regenerative techniques have the potential to radically improve healthcare in the coming years. As a result, there is an emerging need for non-destructive and label-free technologies to assess the quality of engineered tissues and cell-based products prior to their use in the clinic. In parallel, the emerging regenerative medicine industry that aims to produce stem cells and their progeny on a large scale will benefit from moving away from existing destructive biochemical assays towards data-driven automation and control at the industrial scale. Impedance-based cellular assays (IBCA) have emerged as an alternative approach to study stem-cell properties and cumulative studies, reviewed here, have shown their potential to monitor stem-cell renewal, differentiation and maturation. They offer a novel method to non-destructively assess and quality-control stem-cell cultures. In addition, when combined with
in vitro
disease models they provide complementary insights as label-free phenotypic assays. IBCA provide quantitative and very sensitive results that can easily be automated and up-scaled in multi-well format. When facing the emerging challenge of real-time monitoring of three-dimensional cell culture dielectric spectroscopy and electrical impedance tomography represent viable alternatives to two-dimensional impedance sensing.

This article is part of the theme issue ‘Designer human tissue: coming to a lab near you’.
Application of hepatocyte-like cells to enhance hepatic safety risk assessment in drug discovery
Authors: Williams Dominic P.
Published: May 2018

Hepatic stress and injury from drugs continues to be a major concern within the pharmaceutical industry, leading to preclinical and clinical attrition precautionary warnings and post-market withdrawal of drugs. There is a requirement for more predictive and mechanistically accurate models to aid risk assessment. Primary human hepatocytes, subject to isolation stress, cryopreservation, donor-to-donor variation and a relatively short period of functional capability in two-dimensional cultures, are not suitable for high-throughput screening procedures. There are two areas within the drug discovery pipeline that the generation of a stable, metabolically functional hepatocyte-like cell with unlimited supply would have major impact. First, in routine, cell health risk-assessment assays where hepatic cell lines are typically deployed. Second, at later stages of the drug discovery pipeline approaching candidate nomination where bespoke/investigational studies refining and understanding the risk to patients use patient-derived induced pluripotent stem cell (iPSC) hepatocytes retaining characteristics from the patient, e.g. HLA susceptibility alleles, iPSC hepatocytes with defined disease phenotypes or genetic characteristics that have the potential to make the hepatocyte more sensitive to a particular stress mechanism. Functionality of patient-centric hepatocyte-like cells is likely to be enhanced when coupled with emerging culture systems, such as three-dimensional spheroids or microphysiological systems. Ultimately, the aspiration to confidently use human-relevant
in vitro
models to predict human-specific hepatic toxicity depends on the integration of promising emerging technologies.

This article is part of the theme issue ‘Designer human tissue: coming to a lab near you’.
Developing defined substrates for stem cell culture and differentiation
Authors: Hagbard Louise , Cameron Katherine , August Paul , Penton Christopher , Parmar Malin , Hay David C. , Kallur Therése
Published: May 2018

Over the past few decades, a variety of different reagents for stem cell maintenance and differentiation have been commercialized. These reagents share a common goal in facilitating the manufacture of products suitable for cell therapy while reducing the amount of non-defined components. Lessons from developmental biology have identified signalling molecules that can guide the differentiation processin vitro, but less attention has been paid to the extracellular matrix used. With the introduction of more biologically relevant and defined matrices, that better mimic specific cell niches, researchers now have powerful resources to fine-tune theirin vitrodifferentiation systems, which may allow the manufacture of therapeutically relevant cell types. In this review article, we revisit the basics of the extracellular matrix, and explore the important role of the cell–matrix interaction. We focus on laminin proteins because they help to maintain pluripotency and drive cell fate specification.

This article is part of the theme issue ‘Designer human tissue: coming to a lab near you’.
Effects of line orientation in visual evoked potentials. Spatial dynamics, and gender differences of neural oblique effect
Authors: Mikhailova Elena S. , Gerasimenko Natalia Yu. , Slavutskaya Anna V.
Published: May 2018

The aim of the study was to investigate neural mechanisms of orientation discrimination in humans by recording the 128-channel event-related potentials (ERPs) of the brain. Stimuli were black-and-white gratings having four orientations: horizontal, vertical, and oblique 45 and 135 deg. from vertical. Thirty-five healthy subjects (16 males, 19 females) participating in the experiments were asked to differentiate the orientations and push the button. The results showed that the orientation processing consists of two main stages. In the occipital, parietal and temporal areas the P100 and N150 components reflecting the early perceptual stage of processing showed amplitudes greater for oblique orientations than for cardinal ones - “inverse” oblique effect. Further, in the central-parietal and frontal areas the P300 and N400 components reflecting the later cognitive stage of processing showed the “classic” oblique effect with greater amplitudes for cardinal orientations. Females demonstrated lower ERP amplitudes and less pronounced differences between responses elicited by cardinal and oblique orientations. The results suggest that in humans the orientation discrimination occurs in a distributed neural network involving the early sensory as well as higher anterior cortical areas. The classic behavioral oblique effect might be controlled by later processing in the anterior cortical areas. The insufficient neural orientation selectivity observed in females may be considered as the biological basis of their poorer visuospatial abilities.
A double-blinded randomised placebo-controlled phase II trial to evaluate high dose rifampicin for tuberculous meningitis: a dose finding study
Authors: Dian S , Yunivita V , Ganiem AR , Pramaesya T , Chaidir L , Wahyudi K , Achmad TH , Colbers A , te Brake L , van Crevel R , Ruslami R , Aarnoutse R
Published: May 2018

Background

High doses of rifampicin may help tuberculous meningitis (TBM) patients to survive. Pharmacokinetic-pharmacodynamic evaluations suggested that rifampicin doses higher than 13 mg/kg intravenously or 20 mg/kg orally (as previously studied) are warranted to maximize treatment response.

Methods

In a double-blinded, randomised, placebo-controlled phase II trial, we assigned 60 adult TBM patients in Bandung, Indonesia, to standard 450 mg, 900 mg or 1350 mg (10, 20 and 30 mg/kg) oral rifampicin combined with other TB drugs for 30 days. Endpoints included pharmacokinetic measures, adverse events and survival.

Results

A double and triple dose of oral rifampicin led to three and five-fold higher geometric mean total exposures in plasma in the critical early days (2±1) of treatment (AUC0-24h: 53·5 mg.h/L vs 170·6 mg.h/L vs. 293·5 mg.h/L, p<0·001), with proportional increases in CSF concentrations and without an increase in the incidence of grade 3/4 adverse events. Six-month mortality was 7/20 (35%, 9/20 (45%) and 3/20 (15%) in the 10, 20 and 30 mg/kg groups, respectively (p=0·12).

Conclusions

Tripling the standard dose caused a large increase in rifampicin exposure in plasma and CSF and was safe. Survival benefit with this dose should now be evaluated in a larger phase III clinical trial.
The fate of hippocampal synapses depends on the sequence of plasticity-inducing events
Authors: Wiegert J. Simon , Pulin Mauro , Gee Christine E. , Oertner Thomas G.
Published: May 2018

Synapses change their strength in response to specific activity patterns. This functional plasticity is assumed to be the brain’s primary mechanism for information storage. We used optogenetic stimulation of rat hippocampal slice cultures to induce long-term potentiation (LTP), long-term depression (LTD), or both forms of plasticity in sequence. Two-photon imaging of spine calcium signals allowed us to identify stimulated synapses and to follow their fate for the next 7 days. We found that plasticity-inducing protocols affected the synapse’s chance for survival: LTP increased synaptic stability, LTD destabilized synapses, and the effect of the last stimulation protocol was dominant over earlier stimulations. Interestingly, most potentiated synapses were resistant to depression-inducing protocols delivered 24 hours later. Our findings suggest that activity-dependent changes in the transmission strength of individual synapses are transient, but have long-lasting consequences for synaptic lifetime.
Using the Wax moth larvaGalleria mellonellainfection model to detect emerging bacterial pathogens
Authors: Hernandez Rafael J. , Hesse Elze , Dowling Andrea J. , Coyle Nicola M. , Feil Edward J. , Gaze Will H. , Vos Michiel
Published: May 2018

Climate change, changing farming practices, social and demographic changes and rising levels of antibiotic resistance are likely to lead to future increases in opportunistic bacterial infections that are more difficult to treat. Uncovering the prevalence and identity of pathogenic bacteria in the environment is key to assessing transmission risks. We describe the first use of the Wax moth larvaGalleria mellonella, a well-established model for the mammalian innate immune system, to selectively enrich and characterize pathogens from coastal environments in the South West of the U.K. Whole-genome sequencing of highly virulent isolates revealed amongst others aProteus mirabilisstrain carrying theSalmonellaSGI1 genomic island not reported from the U.K. before and the recently described speciesVibrio injenensishitherto only reported from human patients in Korea. Our novel method has the power to detect novel bacterial pathogens in the environment that potentially pose a serious risk to public health.
Extended haplotype phasing of de novo genome assemblies with FALCON-Phase
Authors: Kronenberg Zev N. , Rhie Arang , Koren Sergey , Concepcion Gregory T. , Peluso Paul , Munson Katherine M. , Hiendleder Stefan , Fedrigo Olivier , Jarvis Erich D. , Phillippy Adam M. , Eichler Evan E. , Williams John L. , Smith Tim P.L. , Hall Richard J. , Sullivan Shawn T. , Kingan Sarah B.
Published: May 2018

Haplotype-resolved genome assemblies are important for understanding how combinations of variants impact phenotypes. These assemblies can be created in various ways, such as use of tissues that contain single-haplotype (haploid) genomes, or by co-sequencing of parental genomes, but these approaches can be impractical in many situations. We present FALCON-Phase, which integrates long-read sequencing data and ultra-long-range Hi-C chromatin interaction data of a diploid individual to create high-quality, phased diploid genome assemblies. The method was evaluated by application to three datasets, including human, cattle, and zebra finch, for which high-quality, fully haplotype resolved assemblies were available for benchmarking. Phasing algorithm accuracy was affected by heterozygosity of the individual sequenced, with higher accuracy for cattle and zebra finch (>97%) compared to human (82%). In addition, scaffolding with the same Hi-C chromatin contact data resulted in phased chromosome-scale scaffolds.
Growth zone segmentation in the milkweed bug Oncopeltus fasciatus sheds light on the evolution of insect segmentation
Authors: Auman Tzach , Chipman Ariel D.
Published: May 2018

One of the best studied developmental processes is the Drosophila segmentation cascade. However, this cascade is generally considered to be highly derived and unusual. We present a detailed analysis of the sequential segmentation cascade of the milkweed bug Oncopletus fasciatus, as a comparison to Drosophila, with the aim of reconstructing the evolution of insect segmentation. We analyzed the expression of 12 genes, representing different phases during segmentation. We reconstruct the spatio-temporal relationships among these genes And their roles and position in the cascade. We conclude that sequential segmentation in the Oncopeltus germband includes three phases: Primary pair-rule genes generate segmental gene expression in the anterior growth zone, followed by secondary pair-rule genes, expressed in the transition between the growth zone and the segmented germband. Segment polarity genes are expressed in the segmented germband. This process generates a single-segment periodicity, and does not have a double-segment pattern at any stage.
Infections patterns and fitness effects ofRickettsiaandSodalissymbionts in the green lacewingChrysoperla carnea
Authors: Sontowski Rebekka , Gerth Michael , Richter Sandy , Gruppe Axel , Schlegel Martin , van Dam Nicole , Bleidorn Christoph
Published: May 2018

Endosymbionts are wide-spread among insects and can play an essential role in host ecology. The common green lacewing (Chrysoperla carneas. str.) is a neuropteran insect species which is widely used as a biological pest control. We screened for endosymbionts in natural and laboratory populations of the green lacewing using diagnostic PCR amplicons. We found the endosymbiontRickettsiato be very common in all screened populations, whereas a so far uncharacterizedSodalisstrain was solely found in laboratory populations. The newSodalisstrain was characterized using a whole genome shotgun approach. Its draft genome revealed an approximate genome size of 4.3 Mbp and the presence of 5213 coding sequences. Phylogenomic analyses indicated that this bacterium is the sister taxon ofS. praecaptivus. In an experimental approach, we found a negative impact ofSodalison the reproduction success of the green lacewing. Co-infections withRickettsiaandSodaliscaused an even higher decrease of reproductive success than singleSodalisinfections. In contrast, no significant fitness differences were found inRickettsiainfected green lacewings compared to uninfected lacewings. TheRickettsia/Sodalis/Ch. carneasystem presents a promising model to study evolutionary endosymbiont-host interactions in Neuroptera and endosymbiont-endosymbiont interactions in general. The economic and ecological importance of green lacewings in biological pest control warrants a more profound understanding of its biology, which might be strongly influenced by symbionts.
The connexin 43 regulator Rotigaptide reduces cytokine-induced cell death in human islets
Authors: Ghiasi Seyed Mojtaba , Hansen Jakob Bondo , Christensen Dan Ploug , Mandrup-Poulsen Thomas
Published: May 2018

Abstarct

Background

Intercellular communication mediated by cationic fluxes through the Connexin-family of gap-junctions regulates glucose-stimulated insulin-secretion and beta-cell defense against inflammatory stress. Rotigaptide (RG, ZP123) is a peptide analog that increases intercellular conductance in cardiac muscle-cells by prevention of dephosphorylation and thereby uncoupling of Connexin-43 (Cx43), possibly via action on unidentified protein phosphatases. For this reason, it is being studied in human arrhythmias. It is unknown if RG protects beta-cell function and viability against inflammatory or metabolic stress, a question of considerable translational interest for the treatment of beta-cell failure in diabetes.

Methods

Apoptosis was measured in human islets known to express Cx43, treated with RG or the control peptide ZP119 and exposed to glucolipotoxicity or IL-1b + IFNg. INS-1 cells shown to lack Cx43 were used to verify if RG protected human islet-cells via Cx43-coupling. To study mechanisms of action of Cx43-independent effects of RG, NO, IkBa degradation, mitochondrial activity, ROS and insulin mRNA levels were determined.

Results

RG reduced cytokine-induced apoptosis ~40% in human islets. In Cx43-deficient INS-1 cells this protective effect was markedly blunted as expected, but unexpectedly RG still modestly reduced apoptosis, and improved mitochondrial function, insulin-2 gene levels and accumulated insulin release. RG reduced NO production in Cx43-deficient INS-1 cells associated with reduced iNOS-expression, suggesting that RG blunts cytokine-induced NF-kB signaling in insulin-producing cells in a Cx43-independent manner.

Conclusion

RG reduces cytokine-induced cell-death in human islets. The protective action in Cx43-deficient INS-1 cells suggests a novel inhibitory mechanism of action of RG on NF-kB signaling.
Photodynamic therapy effect on the ultrastructure of Trichomonas vaginalis trophozoites and their effectiveness in experimentally infected animals
Authors: Fonseca Thaisa H.S. , Gomes Jessica M.S. , Alacoque Marina , Vannier-Santos Marcos A. , Gomes Maria A. , Busatti Haendel G.N.O.
Published: May 2018

Background

Trichomonas vaginalis is an amitochondrial parasitic that causes human trichomoniasis, the most common non-viral sexually transmitted infection in the world. The therapy of choice is metronidazole (MTZ). Despite MTZ effectiveness, resistant cases are becoming more frequent. Another point to emphasize are the side effects that may result in treatment discontinuation, leading to further spread of infection and emergence of resistant strains. This scenario reveals the need to develop new therapeutic options. Photodynamic therapy (PDT) is an experimental treatment that involves the activation of photosensitive substances and the generation of cytotoxic oxygen species and free radicals to promote the selective destruction of target tissues. A previous study, from our group, identified an excellent in vitro PDT activity using methylene blue and light emitting diode against MTZ sensitive and resistant strains of T. vaginalis. The aim of this study was to evaluate the efficacy of PDT in vivo and clarify its high trichomonicidal potential by evaluating its action upon T. vaginalis trophozoites through transmission electron microscopy (TEM).

Methodology

Seven-week-old female Balb/c mice were infected intravaginally with T. vaginalis trophozoites. On the third day of infection, methylene blue was introduced into the vaginal canal of the animals, which then received 68.1 J / cm2 of radiation for 35.6 sec. Control groups without infection and infected, treated with metronidazole were also included for comparison. Twenty-four hours after treatment the vaginal canal of the animals was scraped and the samples processed by the immunocytochemistry technique.
After in vitro photodynamic treatment, T. vaginalis trophozoites were processed for TEM. Ultrathin sections were collected in 400-mesh copper grids, contrasted with 5% uranyl acetate and 3% lead citrate, in aqueous solutions for 20 and 5 min., respectively and observed in a Jeol JEM 230 transmission electron microscope.

Results

TEM showed morphological changes such as centripetal displacement of organelles, cannibalism, hydrogenosomal damage, intense cytoplasmic vacuolization, dilated endoplasmic reticulum cisternae and membrane discontinuity, in both resistant and sensitive strains, suggesting that trichomonicidal activity is mainly due to necrosis.

PDT significantly reduced infection in animals treated with a single therapy session, compared to control groups, being statistically as efficient as MTZ.

Conclusions

Our results demonstrated high trichomonicidal activity of PDT with morphological alterations compatible with necrosis. Therefore these results indicate that PDT represents not only an alternative therapy for refractory trichomoniasis, but also routinely for this important neglected parasitic disease.
Reconstruction of consensus tissue-specific metabolic models
Authors: Correia Sara , Costa Bruno , Rocha Miguel
Published: May 2018

Genome-Scale Metabolic Models have shown promising results in biomedical applications, such as understanding cancer metabolism and drug discovery. However, to take full advantage of these models there is the need to address the representation and simulation of the metabolic phenotypes of distinct cell types. With this aim, several algorithms have been recently proposed to reconstruct tissue-specific metabolic models based on available data. Here, the most promising were implemented and used to reconstruct models for two case studies, using omics data from distinct sources. The set of obtained models were compared and analyzed, being shown they are highly variable and that no combination of algorithm and data source can achieve models with acceptable phenotype predictions. We propose an algorithm to achieve a consensus model from the set of models available for a given tissue/cell line, and to improve it given functional data (e.g. known metabolic tasks). The results show that the resulting models are more accurate, both considering the prediction of known metabolic phenotypes and of experimental data not used in the model construction. Two case studies used for model validation consider healthy hepatocytes and a glioblastoma cell line. The open-source implementation of the algorithms is provided, together with the models built, in a software container, allowing full reproducibility, and representing by itself a contribution for the community.
Self-organising coordinate transformation with peaked and monotonic gain modulation in the primate dorsal visual pathway
Authors: Navarro Daniel M. , Mender Bedeho M. W. , Smithson Hannah E. , Stringer Simon M.
Published: May 2018

We study a self-organising neural network model of how visual representations in the primate dorsal visual pathway are transformed from an eye-centred to head-centred frame of reference. The model has previously been shown to robustly develop head-centred output neurons with a standard trace learning rule [1], but only under limited conditions. Specifically it fails when incorporating visual input neurons with monotonic gain modulation by eye-position. Since eye-centred neurons with monotonic gain modulation are so common in the dorsal visual pathway, it is an important challenge to show how efferent synaptic connections from these neurons may self-organise to produce head-centred responses in a subpopulation of postsynaptic neurons. We show for the first time how a variety of modified, yet still biologically plausible, versions of the standard trace learning rule enable the model to perform a coordinate transformation from eye-centred to head-centred reference frames when the visual input neurons have monotonic gain modulation by eye-position.
Healthy Ageing and Sentence Production: Disrupted Lexical Access in the Context of Intact Syntactic Planning
Authors: Hardy Sophie M. , Segaert Katrien , Wheeldon Linda
Published: May 2018

Healthy ageing does not affect all features of language processing equally. In this study, we investigated the effects of ageing on different processes involved in fluent sentence production, a complex task that requires the successful execution and coordination of multiple processes. In Experiment 1, we investigated age-related effects on the speed of syntax selection using a syntactic priming paradigm. Both young and older adults produced target sentences quicker following syntactically related primes compared to unrelated primes, indicating that syntactic facilitation effects are preserved with age. In Experiment 2, we investigated age-related effects in syntactic planning and lexical retrieval using a planning scope paradigm: participants described moving picture displays designed to elicit sentences with either initial coordinate or simple noun phrases and, on half of the trials, the second picture was previewed. Without preview, both age groups were slower to initiate sentences with larger coordinate phrases, suggesting a similar phrasal planning scope. However, age-related differences did emerge relating to the preview manipulation: while young adults displayed speed benefits of preview in both phrase conditions, older adults only displayed speed preview benefits within the initial phrase (coordinate condition). Moreover, preview outside the initial phrase (simple condition) caused older adults to become significantly more error-prone. Thus, while syntactic planning scope appears unaffected by ageing, older adults do appear to encounter problems with managing the activation and integration of lexical items into syntactic structures. Taken together, our findings indicate that healthy ageing disrupts the lexical, but not the syntactic, processes involved in sentence production.
PROTEOME-WIDE ANALYSIS OF CD8+ T CELL RESPONSES TO EBV REVEALS DIFFERENCES BETWEEN PRIMARY AND PERSISTENT INFECTION
Authors: Forrest Calum , Hislop Andrew D. , Rickinson Alan B , Zuo Jianmin
Published: May 2018

ABSTRACT (286 words)

Human herpesviruses are antigenically rich agents that induce strong CD8+T cell responses in primary infection yet persist for life, continually challenging T cell memory through recurrent lytic replication and potentially influencing the spectrum of antigen-specific responses. Here we describe the first lytic proteome-wide analysis of CD8+ T cell responses to the Epstein-Barr gamma1-herpesvirus (EBV), and the first such proteome-wide analysis of primary versus memory CD8 responses to any human herpesvirus. Primary effector preparations were generated directly from activated CD8+ T cells in the blood of infectious mononucleosis (IM) patients by in vitro mitogenic expansion. For memory preparations, EBV-specific cells in the blood of long-term virus carriers were first re-stimulated in vitro by autologous dendritic cells loaded with a lysate of lytically-infected cells, then expanded as for IM cells. Preparations from 7 donors of each type were screened against each of 70 EBV lytic cycle proteins in combination with the donor’s individual HLA class I alleles. Multiple reactivities against immediate early (IE), early (E) and late (L) lytic cycle proteins, including many hitherto unrecognised targets, were detected in both contexts. Interestingly however, the two donor cohorts showed a different balance between IE, E and L reactivities. Primary responses targeted IE and a small group of E proteins preferentially, seemingly in line with their better presentation on the infected cell surface before later-expressed viral evasins take full hold. By contrast, target choice equilibrates in virus carriage with responses to key IE and E antigens still present but with responses to a select subset of L proteins now often prominent. We infer that, for EBV at least, long-term virus carriage with its low level virus replication and lytic antigen release is associated with a re-shaping of the virus-specific response.
Extracellular Electron Transfer by Shewanella oneidensis Controls Pd Nanoparticle Phenotype
Authors: Dundas Christopher M. , Graham Austin J. , Romanovicz Dwight K. , Keitz Benjamin K.
Published: May 2018

Abstarct

Biological production of inorganic materials is impeded by relatively few organisms possessing genetic and metabolic linkage to material properties. The physiology of electroactive bacteria is intimately tied to inorganic transformations, which makes genetically tractable and well-studied electrogens, such as Shewanella oneidensis, attractive hosts for material synthesis. Notably, this species is capable of reducing a variety of transition-metal ions into functional nanoparticles, but exact mechanisms of nanoparticle biosynthesis remain ill-defined. We report two key factors of extracellular electron transfer by S. oneidensis, the outer membrane cytochrome, MtrC, and soluble redox shuttles (flavins), that affect Pd nanoparticle formation. Changes in the expression and availability of these electron transfer components drastically modulated particle phenotype, including particle synthesis rate, structure, and cellular localization. These relationships may serve as the basis for biologically tailoring Pd nanoparticle catalysts and could potentially be used to direct the biogenesis of other metal nanomaterials.
StomataCounter: a neural network for automatic stomata identification and counting
Authors: Fetter Karl C. , Eberhardt Sven , Barclay Rich S. , Wing Scott , Keller Stephen R.
Published: May 2018

Stomata regulate important physiological processes in plants and are often phenotyped by researchers in diverse fields of plant biology. Currently, there are no user friendly, fully-automated methods to perform the task of identifying and counting stomata, and stomata density is generally estimated by manually counting stomata.

We introduce StomataCounter, an automated stomata counting system using a deep convolutional neural network to identify stomata in a variety of different microscopic images. We use a human-in-the-loop approach to train and refine a neural network on a taxonomically diverse collection of microscopic images.

Our network achieves 98.1% identification accuracy on Ginkgo SEM micrographs, and 94.2% transfer accuracy when tested on untrained species.

To facilitate adoption of the method, we provide the method in a publicly available website at http://www.stomata.science/.
Identification and quantification of modified nucleosides inSaccharomyces cerevisiaemRNAs
Authors: Tardu Mehmet , Lin Qishan , Koutmou Kristin S.
Published: May 2018

Post-transcriptional nucleoside modifications have long been recognized as key modulators of non-coding RNA structure and function. There is an emerging appreciation that the chemical modification of protein-coding messenger RNAs (mRNAs) also plays critical roles in the cell. Although there are over 100 known RNA modifications found in biology only a handful have been identified in mRNAs. We sought to identify and quantify modifications present in the mRNAs of yeast cells using a high throughput ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method that measures the levels of 36 types of RNA nucleosides in parallel. We detected the presence of six modified nucleosides in mRNAs at relatively high abundances: N7-methylguanosine, N6-methyladenosine, 2’-O-methylguanosine, 2’-O-methylcytosine, N4-acetylcytidine and 5-formylcytidine. Additionally, we investigated how the levels of mRNA modifications vary in response to cellular stress. We find that the concentrations of mRNA modifications including N6-methyladenosine and N4-acetylcytidine change in response to heat stress, glucose starvation and/or oxidative stress. This work expands the repertoire of potential chemical modifications in mRNAs, and utilizes a high-throughput approach to search for modifications that highlights the value of integrating mass-spectrometry tools in the mRNA modification discovery and characterization pipeline.
Incorporating Context into Language Encoding Models for fMRI
Authors: Jain Shailee , Huth Alexander G
Published: May 2018

Language encoding models help explain language processing in the human brain by learning functions that predict brain responses from the language stimuli that elicited them. Current word embedding-based approaches treat each stimulus word independently and thus ignore the influence of context on language understanding. In this work, we instead build encoding models using rich contextual representations derived from an LSTM language model. Our models show a significant improvement in encoding performance relative to state-of-the-art embeddings in nearly every brain area. By varying the amount of context used in the models and providing the models with distorted context, we show that this improvement is due to a combination of better word embeddings learned by the LSTM language model and contextual information. We are also able to use our models to map context sensitivity across the cortex. These results suggest that LSTM language models learn high-level representations that are related to representations in the human brain.
Mechanism of selective recruitment of RNA polymerases II and III to snRNA gene promoters
Authors: Dergai Oleksandr , Cousin Pascal , Gouge Jerome , Satia Karishma , Praz Viviane , Kuhlman Tracy , Lhôte Philippe , Vannini Alessandro , Hernandez Nouria
Published: May 2018

RNA polymerase II (Pol II) small nuclear RNA (snRNA) promoters and type 3 Pol III promoters have highly similar structures; both contain an interchangeable enhancer and “proximal sequence element” (PSE), which recruits the SNAP complex (SNAPc). The main distinguishing feature is the presence, in the type 3 promoters only, of a TATA box, which determines Pol III specificity. To understand the mechanism by which the absence or presence of a TATA box results in specific Pol recruitment, we examined how SNAPc and general transcription factors required for Pol II or Pol III transcription of SNAPc-dependent genes (i.e., TATA-box-binding protein [TBP], TFIIB, and TFIIA for Pol II transcription and TBP and BRF2 for Pol III transcription) assemble to ensure specific Pol recruitment. TFIIB and BRF2 could each, in a mutually exclusive fashion, be recruited to SNAPc. In contrast, TBP–TFIIB and TBP–BRF2 complexes were not recruited unless a TATA box was present, which allowed selective and efficient recruitment of the TBP–BRF2 complex. Thus, TBP both prevented BRF2 recruitment to Pol II promoters and enhanced BRF2 recruitment to Pol III promoters. On Pol II promoters, TBP recruitment was separate from TFIIB recruitment and enhanced by TFIIA. Our results provide a model for specific Pol recruitment at SNAPc-dependent promoters.
Crystallographic analysis of the Staphylococcus epidermidis lipase involved in esterification in aqueous solution
Authors: Liu Cheng-Huan , Chen Yu-Ting , Hou Ming-Hon , Hu Nien-Jen , Chen Chin-Shuh , Shaw Jei-Fu
Published: May 2018

The Staphylococcus epidermidis lipase (SeLip, GehC) can be used in flavour-compound production via esterification in aqueous solution. This study reports the crystallization and crystallographic analysis of recombinant GehC (rGehC; Lys303–Lys688) with a molecular weight of 43 kDa. rGehC was crystallized at 293 K using PEG 10 000 as a precipitant, and a 99.9% complete native data set was collected from a cooled crystal at 77 K to a resolution of 1.9 Å with an overall R
merge value of 7.3%. The crystals were orthorhombic and belonged to space group P212121, with unit-cell parameters a = 42.07, b = 59.31, c = 171.30 Å, α = β = γ = 90°. Solvent-content calculations suggest that there is likely to be one lipase subunit in the asymmetric unit.
Ownership influence and CSR disclosure in China
Authors: Hu Yuan Yuan , Zhu Yanhui , Tucker Jon , Hu Yuxiao
Published: May 2018

Purpose

This paper aims to examine the relationship between ownership type and the likelihood of publication of a corporate social responsibility (CSR) report.

Design/methodology/approach

Drawing on stakeholder salience theory, the probit model is used for a sample of 1,839 Chinese listed firms to study how different types of owners influence firm CSR engagement.

Findings

The analysis reveals that the Chinese stock exchanges exert a positive influence on the likelihood of a firm producing a CSR report, an effect which is more significant in state-owned enterprises (SOEs). Foreign investors lead to a greater likelihood of publication of a CSR report, though this effect is weaker in SOEs. In contrast, the holdings of state and domestic institutional investors are broadly neutral.

Practical implications

The study helps corporate managers to recognise how particular types of shareholders will value their efforts regarding CSR activities and disclosure and also assists policymakers in improving the level of CSR disclosure through the development of new policy.

Social implications

Apposite CSR disclosure enhances trust and facilitates the shared values on which to build a more cohesive society.

Originality/value

The novelty of this study is that it addresses the effect of institutional investors on Chinese firm CSR engagement and thus provides an important insight for firms, investors and other stakeholders into the interplay of portfolio investment and CSR.
The impact of international financial reporting standards on fund performance
Authors: Rubanov Dmitrij , Nnadi Matthias
Published: May 2018

Purpose

The purpose of this paper is to examine the effect of international financial reporting standards (IFRS) on the performance of UK investment closed-end trust funds with domestic equity focus using Carhart’s Four-Factor model.

Design/methodology/approach

The paper is based on the Efficient Market Hypothesis, which argues that all available information is already included in the price of assets, and therefore, investors cannot beat the market or generate abnormal returns.

Findings

The results show that on average, UK investment trusts neither do generate abnormal returns, nor is their performance persistent. This paper provides empirical evidence to support the efficient market hypotheses and provides proof that the adoption of IFRS has, on average, a decreasing impact on the excess returns generated by UK investment trusts.

Originality/value

The findings of this paper have business policy implications for investment trust in the UK.
Corporate governance and Islamic banks’ products and services disclosure
Authors: Grassa Rihab , Chakroun Raida , Hussainey Khaled
Published: May 2018

Purpose

The purpose of this paper is to examine the determinants of Islamic banks (IBs) product and services disclosure (PSD).

Design/methodology/approach

A computer-based content analysis is run upon the annual reports for a sample of 78 IBs operating in 11 countries from 2004 to 2012 to find the number of product and services statements. The levels and trends of PSD are identified. A regression analysis to identify the factors affecting PSD in IBs is also used.

Findings

The findings suggest that there has been a significant improvement of PSD over time. The results show a positive association between PSD and Shariah board size, board size, chief executive officer (CEO) tenure, duality in position, blockholders and investment account holders. However, they show a negative association between PSD and institutional ownership. In addition, it appears that board independence does not affect significantly banks’ PSD. It is also found that the bank performance, bank age, leverage, listing, adoption of international financial reporting standards, adoption of Accounting and Auditing Organization for Islamic Financial Institutions and country transparency index have a positive effect on the PSD.

Originality/value

This study offers an original contribution to corporate disclosure literature by being the first to develop and investigate PSD for a large sample of IBs during a long period of time. It links P&S with bank corporate governance characteristics. The findings have many important policy implications. More specifically, this paper encourages regulators in the studied countries to improve corporate governance mechanisms in their Islamic banking systems through the optimization of ownership structure, CEO’s characteristics and the board’s characteristics, to promote PSD. Moreover, the findings support the theoretical predictions of the generalized agency theory. This study’s empirical evidence enhances the understanding of the corporate social responsibility disclosure environment in general and the PSD environment in particular for IBs. This study is the first one that measures PSD in the annual reports for a large cross-countries sample of IBs during a long period of time. It is also the first one that links PSD with IBs corporate governance mechanisms.
Legitimising corporate reputation in times of employee distress through disclosure
Authors: Li Zhongtian , Haque Shamima , Chapple Ellie (Larelle)
Published: May 2018

Purpose

This paper aims to examine changes of non-financial voluntary reporting practices over time in response to episodes of employee-related distress. It investigates employee-related disclosures by the four largest electronic manufacturing services firms in China between 2008 and 2013 during a series of employment-related incidents, to investigate how the firms re-legitimate their reputation in response to the media coverage on those incidents.

Design/methodology/approach

A series of employee-related incidents that occurred in 2010-2012 is selected as the focus of this study, with total coverage of employee-related disclosures between 2008 and 2013. These incidents are directly linked to three of the four sample companies: Foxconn, Pegatron and Compal Electronics. Employee-related disclosures in corporate social responsibility (CSR) stand-alone reports are coded by a set of specifically designed instructions, and newspaper articles about employee-related incidents are coded for sentiment. Results are interpreted through two theoretical lenses: the media agenda setting theory and the legitimacy theory.

Findings

Newspapers reported the employee-related incidents in a way detrimental to the legitimacy of firms that directly involved in the selected industry. In the process of legitimation, firms switch between disclosing more employee-related information and reducing disclosures. The self-expectation on organizational legitimacy also affects how CSR reporting is used in legitimation. The employee-related disclosure analysed is closer to symbolic legitimation than substantive legitimation.

Originality/value

This study contributes to reporting practice by showing that employee-related disclosure is largely vacuous and to a greater extent is used as symbolic legitimation. The quality of disclosure requires significant improvement. This study contributes to the literature by using the legitimacy theory to interpret employee-related disclosure in China, addressing inadequate research efforts in the context of social and human rights dimensions of CSR reporting.
Clinical and immunological effects of adsorptive myeloid lineage leukocyte apheresis in patients with immune disorders
Authors: Kanekura Takuro
Published: May 2018

Adsorptive granulocyte and monocyte apheresis (GMA) with the Adacolumn® is an extracorporeal treatment, which uses cellulose acetate (CA) beads as adsorptive leukocytapheresis carriers designed to remove elevated and potentially activated myeloid lineage leukocytes. Reports on the clinical efficacy of GMA in patients with skin lesions have appeared in the published work. Dermatological diseases, which are known to respond to GMA, include pyoderma gangrenosum, skin lesions of Behçet's disease, rheumatoid arthritis, pustular psoriasis, psoriatic arthritis, adult‐onset Still's disease, Sweet's syndrome, cutaneous allergic vasculitis and systemic lupus erythematosus rashes. In association with clinical studies, efforts to understand the mechanisms of GMA have made significant progress. GMA selectively depletes elevated myeloid lineage leukocytes through binding between blood immunoglobulin G or complement iC3b, which form on the surface of CA beads and the Fcγ receptors or complement receptors expressed on the myeloid lineage cells. However, GMA has immunomodulatory effects including down‐modulation of inflammatory cytokine profile, changes in leukocyte surface receptors and induction of regulatory T cells. These actions render GMA a unique non‐pharmacological treatment option for patients with chronic dermatoid conditions, which are difficult to treat with pharmacological preparations.
Comparative analgesic efficacy of pregabalin administered according to either a prevention protocol or an intervention protocol in rats with cisplatin‐induced peripheral neuropathy
Authors: Han Felicity Y , Kuo Andy , Nicholson Janet R , Corradinni Laura , Smith Maree T
Published: May 2018

Chemotherapy‐induced peripheral neuropathy (CIPN) is a type of peripheral neuropathic pain that may be dose‐limiting in patients administered potentially curative cancer chemotherapy dosing regimens. In cancer survivors, persistent CIPN adversely affects patient quality of life and so adjuvant drugs (anticonvulsants eg pregabalin or antidepressants eg amitriptyline) are recommended for the relief of CIPN. However, most studies in rodent models of CIPN involve administration of single bolus doses of adjuvant drugs to assess pain‐relieving efficacy. Hence this study was designed to assess the efficacy of pregabalin administered to CIPN‐rats according to either a prevention or an intervention protocol. Groups of male Sprague‐Dawley rats received four single intraperitoneal bolus doses of cisplatin at 3 mg/kg at once‐weekly intervals to induce CIPN. For the prevention protocol, oral pregabalin (or vehicle) was administered to CIPN‐rats once‐daily for 21 consecutive days from day 0 to day 20 inclusive. For the intervention protocol, oral pregabalin was administered once‐daily for 21 consecutive days from day 28 to day 48, inclusive. Mechanical allodynia and mechanical hyperalgesia in the bilateral hindpaws were assessed just prior to each dose of cisplatin and at least once weekly until study completion (day 27, prevention protocol; or day 48, intervention protocol). Mechanical allodynia and mechanical hyperalgesia were also determined at the time of peak effect at about 2 hours post pregabalin/vehicle administration, once weekly until study completion. For the prevention protocol in CIPN‐rats, pregabalin alleviated mechanical hyperalgesia but not mechanical allodynia. For the intervention protocol, pregabalin alleviated both mechanical allodynia and mechanical hyperalgesia in the hindpaws.