bluuebunny/crossref_metadata_2025 huggingface dataset:
Inflammatory and Comorbid Features of Children Admitted to a PICU for Status Asthmaticus*
Authors: Grunwell Jocelyn R. , Travers Curtis , Fitzpatrick Anne M.
Published: August 2018

Objectives:

To determine risk factors associated with admission to a PICU with or without endotracheal intubation for an asthma exacerbation. We hypothesized that children with critical and near-fatal asthma would have distinguishing clinical features but varying degrees of asthma severity and measures of type 2 inflammation.

Design:

Retrospective analysis of prospectively collected data of children with asthma recruited into outpatient asthma clinical research studies at Emory University between 2004 and 2015.

Setting:

Large, free-standing academic quaternary care children’s hospital in Atlanta, GA.

Patients:

Children 6–18 years old with physician-diagnosed and confirmed asthma.

Interventions:

None.

Measurements and Main Results:

A total of 579 children were analyzed with 170 children (29.4%) being admitted to the PICU for an asthma exacerbation in their lifetime. Of these 170 children with a history of critical asthma, 24.1% were classified as having mild-to-moderate asthma, and 83 of 170 children (48.8%) had been intubated and experienced near-fatal asthma. Multiple logistic regression was used to identify risk factors associated with increased odds of PICU admission with or without endotracheal intubation. Hospitalization within the prior 12 months of survey (odds ratio, 8.19; 95% CI, 4.83–13.89), a history of pneumonia (odds ratio, 2.56; 95% CI, 1.52–4.29), having a designation of increased chronic asthma severity on high-dose inhaled corticosteroids (odds ratio, 2.76; 95% CI, 1.62–4.70), having a father with asthma (odds ratio, 2.15; 95% CI, 1.23–3.76), living in a region with a higher burden of poverty (odds ratio, 1.28; 95% CI, 1.02–1.61), and being of black race (odds ratio, 2.01; 95% CI, 1.05–3.84) were all associated with increased odds of PICU admission with or without intubation.

Conclusions:

Our findings suggest that there are factors associated with critical and near-fatal asthma, distinct from the chronic asthma severity designations, that should be the focus of future investigation.
Adverse Drug Event–Related Admissions to a Pediatric Emergency Unit
Authors: Carvalho Indira Valadê , de Sousa Vanessa Marcilio , Visacri Marília Berlofa , Quintanilha Júlia Coelho França , de Souza Cinthia Madeira , Ambrósio Rosiane Fátima Lopes , Reis Marcelo Conrado dos , de Queiroz Rachel Alvarenga , Mazzola Priscila Gava , Galvao Taís Freire , Moriel Patricia
Published: August 2018

Objectives

The objectives of this study were to analyze adverse drug events (ADEs) related to admissions to a pediatric emergency unit and to identify the associated risk factors.

Methods

This was a prospective study. Demographic data and details of medications were collected for each patient admitted. Case studies were performed by clinical pharmacists and the clinical team to discuss whether the admission was due to an ADE and to characterize the ADE. Multivariate logistic regression was used for statistical analysis.

Results

In total, 1708 pediatric patients were included in this study. Adverse drug events were the cause of hospital admission in 12.3% of the studied population. The majority of patients presenting with an ADE were in the age group of 0 to 5 years (61.6%), had a mean ± SD age of 4.9 ± 3.9 years, were female (51.2%), were Caucasian (72.0%), and had infectious disorders (49.3%). High frequencies of medication errors (68.8%), use of drugs to treat respiratory disorders (27.7%), and ADEs of mild severity (75.3%) were reported. The risk of being admitted to the pediatric emergency unit for any ADE increased in cases of neurological (odds ratio [OR], 4.63; 95% confidence interval [CI], 2.38–8.99), dermatological (OR, 3.16; 95% CI, 1.93–5.18), and respiratory (OR, 3.02; 95% CI, 1.89–4.83) disorders.

Conclusions

A high frequency of ADE-related admissions to the pediatric emergency unit was observed. The risk of being admitted to the pediatric emergency unit for any ADE increased in cases of neurological, dermatological, and respiratory disorders. Clinical pharmacists play an important role in the identification of ADEs and the education of child caregivers and health care providers concerning pediatric medication.
Double Reading of Outsourced CT/MR Radiology Reports: Retrospective Analysis
Authors: Vendrell Jean-François , Frandon Julien , Boussat Bastien , Cotton François , Ferretti Gilbert , Sans Nicolas , Tasu Jean-Pierre , Beregi Jean-Paul , Larbi Ahmed
Published: August 2018

Objectives

Our objective was to determine disagreement rates in radiological reports provided by using a double-reading protocol in a national teleradiology company.

Methods

From January 2015 to July 2016, 134169 radiological exams from 36 French centers, benefited outsourced interpretations by certified radiologists, in both regular and after-hours activities. Of these, 2040 CT and MR-scans (1.5%) were subjected to a second opinion by other radiologists in the field of their anatomical specialty (cerebral, thoracic, abdominal-pelvic, and osteoarticular). A five-point agreement scale graded from 0 to 4 was assigned for each exam. Disagreements were considered as minor if no clinical consequence for patient (scores 1 and 2) and major if potential clinical consequence (score 3 and 4). Independent radiologists performed a retrospective analysis and a stratified statistical analysis.

Results

Double reading was performed on CT-scans (n = 934/2040, 45.8%) and MR-scans (n = 1106/2040, 54.2%) performed in regular (80.1%) and after-hours activities (19.9%). Disagreement scores occurred in 437 exams (21.4%), including major disagreements in 59 (2.9%). Among these, 48/754 were assigned by the thoracic second reader (6.4%), 6/70 by the abdominal-pelvic second reader (8.6%), 3/901 by the osteoarticular second reader (0.3%), and 2/315 by the cerebral second reader (0.6%), with statistical significant difference. No additional disagreement rate was observed in regular and after-hours activities (P = 0.63).

Conclusions

Double-reading of outsourced CT and MRI interpretations yielded 21.4% disagreement rate, with potential clinical consequence for patient in 2,9% of the cases. These results are in accordance with those previously reported and suggests that quality assurance of outsourced interpretations is needed.
Digital-Facial Translocation in Amniotic Band Sequence: Evidence of the Intrinsic Theory
Authors: Weinstein Brielle , Hassouba Mahmoud , Flores Roberto L. , Staffenberg David A. , Gordon Christopher B. , Runyan Christopher M.
Published: August 2018

Amniotic band sequence is a complex congenital anomaly in which infants with typically no known genetic mutation have bands of maternal amniotic tissue wrapped around body parts, most commonly the limbs and digits. The authors report a novel variation on this presentation in 3 patients from 2 centers with complex craniofacial clefting and amniotic band sequence. They presented with hypertelorism, different forms of complex craniofacial clefting, and bands connecting ipsilateral hands to facial clefts, with digital-facial translocation in 2 cases. These findings support a model in which complex craniofacial clefts result in areas of exposed, sticky, and temporally and spatially coincident mesenchyme within the embryo that are susceptible to adherence of ipsilateral fetal hands. This strongly supports the intrinsic and adhesion theories of the etiology of amniotic band syndrome.
Lingual Nerve Entrapment in Fused Submandibular and Sublingual Salivary Glands: A Unique Finding
Authors: Nayak Satheesha B. , Kumar Naveen
Published: August 2018

Lingual nerve (LN) is one among the 3 branches of posterior division of mandibular nerve. It might get entrapped in the infratemporal fossa by lateral pterygoid muscle, pterygospinous ligament, or lateral pterygoid plate. Its entrapment in the submandibular region has not been reported yet. A unique entrapment of LN in the fused submandibular and sublingual salivary glands in a cadaver was reported. The deep parts of the submandibular and sublingual salivary glands were completely fused with each other. The LN passed through the center of the fused part. Histologically both submandibular and sublingual salivary glands had both mucous and serous acini. Though this entrapment might not cause any functional problems, it might get injured during various surgical procedures of the submandibular region.
Retained Eyeglasses in the Orbital Cavity After Penetrating Facial Trauma
Authors: Kim Seon Tae , Jung Joo Hyun , Lim Byeong Woo , Ha Ryun , Woo Joo Hyun , Cha Heung Eog , Chi Mijung , Chang Jin Soon , Kang Il Gyu
Published: August 2018

This study describes a 68-year-old man who was presented to the emergency department with left orbital cavity penetration by his eyeglasses. The eyeglasses had entered the orbit and at presentation his eyesight could not be measured. The foreign body was extracted carefully and panfacial bone fractures were then reduced through lateral rhinotomy combined with a lip-splitting incision. When planning removal of an unusual foreign body from the orbital cavity, care should be taken not to injure the optic nerve, periorbital musculatures, or the eyeball.
Toward a Sensible Single-antigen Bead Cutoff Based on Kidney Graft Survival
Authors: Wisse Bram W. , Kamburova Elena G. , Joosten Irma , Allebes Wil A. , van der Meer Arnold , Hilbrands Luuk B. , Baas Marije C. , Spierings Eric , Hack Cornelis E. , van Reekum Franka E. , van Zuilen Arjan D. , Verhaar Marianne C. , Bots Michiel L. , Drop Adriaan C.A.D. , Plaisier Loes , Seelen Marc A.J. , Stephan Sanders Jan , Hepkema Bouke G. , Lambeck Annechien J.A. , Bungener Laura B. , Roozendaal Caroline , Tilanus Marcel G.J. , Voorter Christina E. , Wieten Lotte , van Duijnhoven Elly M. , Gelens Mariëlle A.C.J. , Christiaans Maarten H.L. , van Ittersum Frans J. , Nurmohamed Shaikh A. , Lardy Neubury M. , Swelsen Wendy , van der Pant Karlijn A.M.I. , van der Weerd Neelke C. , ten Berge Ineke J.M. , Bemelman Frederike J. , Hoitsma Andries J. , van der Boog Paul J.M. , de Fijter Johan W. , Betjes Michiel G.H. , Heidt Sebastiaan , Roelen Dave L. , Claas Frans H. , Otten Henny G.
Published: August 2018

Background.

There is no consensus in the literature on the interpretation of single-antigen bead positive for a specific HLA antibody.

Methods.

To inform the debate, we studied the relationship between various single-antigen bead positivity algorithms and the impact of resulting donor-specific HLA antibody (DSA) positivity on long-term kidney graft survival in 3237 deceased-donor transplants.

Results.

First, we showed that the interassay variability can be greatly reduced when working with signal-to-background ratios instead of absolute median fluorescence intensities (MFIs). Next, we determined pretransplant DSA using various MFI cutoffs, signal-to-background ratios, and combinations thereof. The impact of the various cutoffs was studied by comparing the graft survival between the DSA-positive and DSA-negative groups. We did not observe a strong impact of various cutoff levels on 10-year graft survival. A stronger relationship between the cutoff level and 1-year graft survival for DSA-positive transplants was found when using signal-to-background ratios, most pronounced for the bead of the same HLA locus with lowest MFI taken as background.

Conclusions.

With respect to pretransplant risk stratification, we propose a signal-to-background ratio-6 (using the bead of the same HLA-locus with lowest MFI as background) cutoff of 15 combined with an MFI cutoff of 500, resulting in 8% and 21% lower 1- and 10-year graft survivals, respectively, for 8% DSA-positive transplants.
Realistic in silico generation and augmentation of single cell RNA-seq data using Generative Adversarial Neural Networks
Authors: Marouf Mohamed , Machart Pierre , Bansal Vikas , Kilian Christoph , Magruder Daniel S. , Krebs Christian F. , Bonn Stefan
Published: August 2018

A fundamental problem in biomedical research is the low number of observations available, mostly due to a lack of available biosamples, prohibitive costs, or ethical reasons. Augmenting few real observations with generated in silico samples could lead to more robust analysis results and a higher reproducibility rate. Here we propose the use of conditional single cell Generative Adversarial Neural Networks (cscGANs) for the realistic generation of single cell RNA-seq data. cscGANs learn non-linear gene-gene dependencies from complex, multi cell type samples and use this information to generate realistic cells of defined types. Augmenting sparse cell populations with cscGAN generated cells improves downstream analyses such as the detection of marker genes, the robustness and reliability of classifiers, the assessment of novel analysis algorithms, and might reduce the number of animal experiments and costs in consequence. cscGANs outperform existing methods for single cell RNA-seq data generation in quality and hold great promise for the realistic generation and augmentation of other biomedical data types.
Cyclin B3 is specifically required for metaphase to anaphase transition in mouse oocyte meiosis I
Authors: Li Yufei , Wang Leyun , Zhang Linlin , He Zhengquan , Feng Guihai , Sun Hao , Wang Jiaqiang , Li Zhikun , Liu Chao , Han Jiabao , Mao Junjie , Yuan Xuewei , Jiang Liyuan , Zhang Ying , Zhou Qi , Li Wei
Published: August 2018

Meiosis, a cell division to generate gametes for sexual reproduction in eukaryotes, executes a single round of DNA replication and two successive rounds of chromosome segregation [1]. The extraordinary reliability of the meiotic cycle requires the activities of cyclin-dependent kinases (Cdks) associated with specific cyclins [2-4]. Cyclins are the regulatory subunits of protein kinases, which are the main regulators of maturation promoting factor or mitosis promoting factor (MPF) [5, 6] and anaphase-promoting complex/cyclosome (APC/C) [7, 8] in eukaryotic cell division. But how cyclins collaborate to control meiosis is still largely unknown. Cyclin B3 (Ccnb3) shares homology with A- and B-type cyclins [9], and is conserved during higher eukaryote evolution [10-17]. Previous studies have shown thatCcnb3-deleted females are sterile with oocytes unable to complete meiosis I inDrosophila[18], implying that Ccnb3 may have a special role in meiosis. To clarify the function of Ccnb3 in meiosis in mammalian species, we generatedCcnb3mutant mice by CRISPR/Cas9, and found thatCcnb3mutation caused female infertility with the failure of metaphase-anaphase transition in meiosis I. Ccnb3 was necessary for APC/C activation to initiate anaphase I, but not required for oocytes maturation, meiosis II progression, or early embryonic development. Our study reveals the differential cell cycle regulation between meiosis I and meiosis II, as well as meiosis between males and females, which shed light on the cell cycle control of meiosis.

Highlights

Identification of a female meiosis-specific cyclin in mouse

Cyclin B3 is required for metaphase-anaphase transition in oocyte meiosis I

Cyclin B3 is not essential for oocyte maturation and sister chromosome segregation

Cyclin B3 is necessary for APC/C activation and MPF kinase activity through Cdk1
Whole-genome sequencing of three native cattle breeds originating from the northernmost cattle farming regions
Authors: Weldenegodguad Melak , Popov Ruslan , Pokharel Kisun , Ammosov Innokentyi , Yao Ming , Ivanova Zoya , Kantanen Juha
Published: August 2018

Northern Fennoscandia and the Sakha Republic in the Russian Federation represent the northernmost regions on Earth where cattle farming has been traditionally practiced. In this study, we performed whole-genome resequencing to genetically characterize three rare native breeds Eastern Finncattle, Western Finncattle and Yakutian cattle adapted to these northern Eurasian regions. We examined the demographic history, genetic diversity and unfolded loci under natural or artificial selection. On average, we achieved 13.01-fold genome coverage after mapping the sequencing reads on the bovine reference genome (UMD 3.1) and detected a total of 17.45 million single nucleotide polymorphisms (SNPs) and 1.95 million insertions-deletions (indels). We observed that the ancestral species (Bos primigenius) of Eurasian taurine cattle experienced two notable prehistorical declines in effective population size associated with dramatic climate changes. The modern Yakutian cattle exhibited a higher level of within-population variation in terms of number of SNPs and nucleotide diversity than the contemporary European taurine breeds. This result is in contrast to the results of marker-based cattle breed diversity studies, indicating assortment bias in previous analyses. Our results suggest that the effective population size of the ancestral Asiatic taurine cattle may have been higher than that of the European cattle. Alternatively, our findings could indicate the hybrid origins of the Yakutian cattle ancestries and possibly the lack of intensive artificial selection. We identified a number of genomic regions under selection that may have contributed to the adaptation to the northern and subarctic environments, including genes involved in disease resistance, sensory perception, cold adaptation and growth. By characterizing the native breeds, we were able to obtain new information on cattle genomes and on the value of the adapted breeds for the conservation of cattle genetic resources.
Mitochondria-encoded genes contribute to the evolution of heat and cold tolerance amongSaccharomycesspecies
Authors: Li Xueying C. , Peris David , Hittinger Chris Todd , Sia Elaine A. , Fay Justin C.
Published: August 2018

Over time, species evolve substantial phenotype differences. Yet, genetic analysis of these traits is limited by reproductive barriers to those phenotypes that distinguish closely related species. Here, we conduct a genome-wide non-complementation screen to identify genes that contribute to a major difference in thermal growth profile between twoSaccharomycesspecies.S. cerevisiaeis capable of growing at temperatures exceeding 40°C, whereasS. uvarumcannot grow above 33°C but outperformsS. cerevisiaeat 4°C. The screen revealed only a single nuclear-encoded gene with a modest contribution to heat tolerance, but a large effect of the species’ mitochondrial DNA (mitotype). Furthermore, we found that, while theS. cerevisiaemitotype confers heat tolerance, theS. uvarummitotype confers cold tolerance. Recombinant mitotypes indicate multiple genes contribute to thermal divergence. Mitochondrial allele replacements showed that divergence in the coding sequence ofCOX1has a moderate effect on both heat and cold tolerance, but it does not explain the entire difference between the two mitochondrial genomes. Our results highlight a polygenic architecture for interspecific phenotypic divergence and point to the mitochondrial genome as an evolutionary hotspot for not only reproductive incompatibilities, but also thermal divergence in yeast.
Reactive Centre Loop Dynamics and Serpin Specificity
Authors: Marijanovic Emilia M. , Fodor James , Riley Blake T. , Porebski Benjamin T. , Costa Mauricio G. S. , Kass Itamar , Hoke David E. , McGowan Sheena , Buckle Ashley M.
Published: August 2018

Serine proteinase inhibitors (serpins), typically fold to a metastable native state and undergo a major conformational change in order to inhibit target proteases. However, conformational labiality of the native serpin fold renders them susceptible to misfolding and aggregation, and underlies misfolding diseases such as a1-antitrypsin deficiency. Serpin specificity towards its protease target is dictated by its flexible and solvent exposed reactive centre loop (RCL), which forms the initial interaction with the target protease during inhibition. Previous studies have attempted to alter the specificity by mutating the RCL to that of a target serpin, but the rules governing specificity are not understood well enough yet to enable specificity to be engineered at will. In this paper, we useconserpin, a synthetic, thermostable serpin, as a model protein with which to investigate the determinants of serpin specificity by engineering its RCL. Replacing the RCL sequence with that from α1-antitrypsin fails to restore specificity against trypsin or human neutrophil elastase. Structural determination of the RCL-engineered conserpin and molecular dynamics simulations indicate that, although the RCL sequence may partially dictate specificity, local electrostatics and RCL dynamics may dictate the rate of insertion during protease inhibition, and thus whether it behaves as an inhibitor or a substrate. Engineering serpin specificity is therefore substantially more complex than solely manipulating the RCL sequence, and will require a more thorough understanding of how conformational dynamics achieves the delicate balance between stability, folding and function required by the exquisite serpin mechanism of action.
Transcriptomic response in symptomless roots of clubroot infected kohlrabi (Brassica oleracea var. gongylodes) mirrors resistant plants
Authors: Ciaghi Stefan , Schwelm Arne , Neuhauser Sigrid
Published: August 2018

Background

Clubroot disease caused by Plasmodiophora brassicae (Phytomyxea, Rhizaria) is one of the economically most important diseases of Brassica crops. The formation of hypertrophied roots accompanied by altered metabolism and hormone homeostasis is typical for infected plants. Not all roots of infected plants show the same phenotypic changes. While some roots remain uninfected, others develop galls of diverse size. The aim of this study was to analyse and compare the intra-plant heterogeneity of P. brassicae root galls and symptomless roots of the same host plants (Brassica oleracea var. gongylodes) collected from a commercial field in Austria using transcriptome analyses.

Results

Transcriptomes were markedly different between symptomless roots and gall tissue. Symptomless roots showed transcriptomic traits previously described for resistant plants. Genes involved in host cell wall synthesis and reinforcement were up-regulated in symptomless roots indicating elevated tolerance against P. brassicae. By contrast, genes involved in cell wall degradation and modification processes like expansion were up-regulated in root galls. Hormone metabolism differed between symptomless roots and galls. Brassinosteroid-synthesis was down-regulated in root galls, whereas jasmonic acid synthesis was down-regulated in symptomless roots. Cytokinin metabolism and signalling were up-regulated in symptomless roots with the exception of one CKX6 homolog, which was strongly down-regulated. Salicylic acid (SA) mediated defence response was up-regulated in symptomless roots, compared with root gall tissue. This is probably caused by a secreted benzoic acid salicylic acid methyl transferase from the pathogen (PbBSMT), which was one of the highest expressed pathogen genes in gall tissue. The PbBSMT derived Methyl-SA potentially leads to increased pathogen tolerance in uninfected roots.

Conclusions

Infected and uninfected roots of clubroot infected plants showed transcriptomic differences similar to those previously described between clubroot resistant and susceptible hosts. The here described intra-plant heterogeneity suggests, that for a better understanding of clubroot disease targeted, spatial analyses of clubroot infected plants will be vital in understanding this economically important disease.
Maintaining trunk neural crest cells as crestospheres
Authors: Mohlin Sofie , Kunttas Ezgi , Persson Camilla U. , Abdel-Haq Reem , Castillo Aldo , Murko Christina , Bronner Marianne E. , Kerosuo Laura
Published: August 2018

Neural crest cells have broad migratory and differentiative ability that differs according to their axial level of origin. However, their transient nature has limited understanding of their stem cell and self-renewal properties. While anin vitroculture method has made it possible to maintain cranial neural crest cells as self-renewing multipotent crestospheres (Kerosuo et al., 2015), these same conditions failed to preserve trunk neural crest in a stem-like state. Here we optimize culture conditions for maintenance of trunk crestospheres, comprised of both neural crest stem and progenitor cells. Trunk crestospheres display elevated expression of neural crest cell markers as compared to those characteristic of neural tube or mesodermal fates. Moreover, trunk crestospheres have increased expression of trunk-related markers as compared to cranial genes. Finally, we use lentiviral transduction as a tool to manipulate gene expression in trunk crestospheres. Taken together, this method enables long-termin vitromaintenance and manipulation of trunk neural crest cells in a premigratory stem or early progenitor state to probe the mechanisms underlying their stemness and lineage decisions.

Highlights

Trunk-derived multipotent neural crest stem cells can be cultured as crestospheres

Trunk-derived crestospheres require different conditions than cranial

Trunk crestospheres consist of neural crest stem and progenitor cells

Trunk crestospheres can be efficiently transduced using lentiviral vectors
Supra-threshold psychoacoustics and envelope-following response relations: normal-hearing, synaptopathy and cochlear gain loss
Authors: Verhulst Sarah , Ernst Frauke , Garrett Markus , Vasilkov Viacheslav
Published: August 2018

The perceptual consequences of cochlear synaptopathy are presently not well understood as a direct quantification of synaptopathy is not possible in humans. To study its role for human hearing, recent studies have instead correlated changes in basic supra-threshold psychoacoustic tasks with individual differences in subcortical EEG responses, as a proxy measure for synaptopathy. It is not clear whether the reported missing relationships between the psychoacoustic quantities and the EEG are due to the adopted methods, or to a minor role of synaptopathy for sound perception. We address this topic by studying the theoretical relationship between subcortical EEG and psychoacoustic methods for different sensorineural hearing deficits.
Proteomic analysis of RNA-dependent chromatin association of nuclear proteins
Authors: Hiragami-Hamada Kyoko , Tani Naoki , Nakayama Jun-ichi
Published: August 2018

Various coding and non-coding transcripts are known to associate with chromatin and now there is accumulating evidence that interaction between RNA-binding proteins (RBPs) and RNA molecules regulate not only co-transcriptional mRNA processing, but also other biological processes within the nucleus. Although over a thousand of RBPs have been identified by several mass spectrometry-based methods, it is still unclear which of these RBPs actually associate with chromatin, especially through interaction with RNAs. In addition, biological outcomes of such RBP-RNA-chromatin interactions are yet to be elucidated.

Here we describe a simple proteomics-based method for systematic screening of RBPs that are anchored to chromatin and/or insoluble nuclear substructures by RNA molecules. We used RNase A to release such RBPs from chromatin fraction and analyzed ‘RNase A-solubilized’ proteins by mass spectrometry. Using this method, we were able to identify 156 RNase A-solubilized proteins of which 144 were known RBPs/RBP candidates. Interestingly, several key players of the non-homologous end-joining (NHEJ) pathway were enriched in RNase A-solubilized fraction and the RNA-mediated chromatin association of these factors appeared to be dependent on transcriptional elongation. Furthermore, some enzymes involved in metabolic pathways were also released from chromatin and/or an insoluble nuclear structure by RNase A treatment. In summary, our methodology is highly versatile and is potentially a useful tool to unravel new biological functions for RBP-RNA-chromatin interactions.
Cortical circuit alterations precede disease onset in Huntington’s disease mice
Authors: Neuner Johanna , Schulz-Trieglaff Elena Katharina , Gutiérrez-Ángel Sara , Hosp Fabian , Mann Matthias , Arzberger Thomas , Klein Rüdiger , Liebscher Sabine , Dudanova Irina
Published: August 2018

Huntington’s disease (HD) is a devastating hereditary movement disorder, characterized by degeneration of neurons in the striatum and cortex. Studies in human patients and mouse HD models suggest that disturbances of neuronal function in the neocortex play an important role in the disease onset and progression. However, the precise nature and time course of cortical alterations in HD have remained elusive. Here, we use chronicin vivotwo-photon calcium imaging to monitor the activity of single neurons in layer 2/3 of the primary motor cortex in awake, behaving R6/2 transgenic HD mice and wildtype littermates. R6/2 mice show age-dependent changes in neuronal activity with a clear increase in activity at the age of 8.5 weeks, preceding the onset of motor and neurological symptoms. Furthermore, quantitative proteomics demonstrate a pronounced downregulation of synaptic proteins in the cortex, and histological analyses in R6/2 mice and HD patient samples reveal reduced inputs from parvalbumin-positive interneurons onto layer 2/3 pyramidal cells. Thus, our study provides a time-resolved description as well as mechanistic details of cortical circuit dysfunction in HD.

Significance statement

Funtional alterations in the cortex are believed to play an important role in the pathogenesis of Huntington’s disease (HD). However, studies monitoring cortical activity in HD modelsin vivoat a single-cell resultion are still lacking. We have used chronic two-photon imaging to investigate changes in the activity of single neurons in the primary motor cortex of awake presymptomatic HD mice. We show that neuronal activity increases before the mice develop disease symptoms. Our histological analyses in mice and in human HD autopsy cases furthermore demonstrate a loss inhibitory synaptic terminals from parvalbimun-positive interneurons, revealing a potential mechanism of cortical circuit impairment in HD.
Uncoupled activation and cyclisation in catmint reductive terpenoid biosynthesis
Authors: Lichman Benjamin R , Kamileen Mohamed O , Titchiner Gabriel R , Saalbach Gerhard , Stevenson Clare E M , Lawson David M , O’Connor Sarah E
Published: August 2018

Terpene synthases typically form complex molecular scaffolds by concerted activation and cyclization of linear starting materials in a single enzyme active site. Here we show that iridoid synthase, an atypical reductive terpene synthase, catalyses the activation of its substrate 8-oxogeranial into a reactive enol intermediate but does not catalyse the subsequent cyclisation into nepetalactol. This discovery led us to identify a class of nepetalactol-related short-chain dehydrogenase enzymes (NEPS) from catmint (Nepeta mussinii) which catalyse the stereoselective cyclisation of the enol intermediate into nepetalactol isomers. Subsequent oxidation of nepetalactols by NEPS1 provides nepetalactones, metabolites that are well known for both insect-repellent activity and euphoric effect in cats. Structural characterisation of the NEPS3 cyclase reveals it binds to NAD+ yet does not utilise it chemically for a non-oxidoreductive formal [4+2] cyclisation. These discoveries will complement metabolic reconstructions of iridoid and monoterpene indole alkaloid biosynthesis.
Sequence-to-structure dependence of isolated IgG Fc complex biantennary N-glycans: A molecular dynamics study
Authors: Harbison Aoife M , Brosnan Lorna P , Fenlon Keith , Fadda Elisa
Published: August 2018

Fc glycosylation of human immunoglobulins G (IgGs) is essential for their structural integrity and activity. Interestingly, the specific nature of the Fc glycoforms is known to modulate the IgG effector function. Indeed, while core-fucosylation of IgG Fc-glycans greatly affects the antibody-dependent cell-mediated cytotoxicity (ADCC) function, with obvious repercussions in the design of therapeutic antibodies, sialylation can reverse the antibody inflammatory response, and galactosylation levels have been linked to aging, to the onset of inflammation, and to the predisposition to rheumatoid arthritis. Within the framework of a structure-to-function relationship, we have studied the role of the N-glycan sequence on its intrinsic conformational propensity. Here we report the results of a systematic study, based on extensive molecular dynamics (MD) simulations in excess of 62 µs of cumulative simulation time, on the effect of sequence on the structure and dynamics of increasingly larger, complex biantennary N-glycoforms, i.e. from chitobiose to the larger N-glycan species commonly found in the Fc region of human IgGs. Our results show that while core fucosylation and sialylation do not affect the intrinsic dynamics of the isolated (unbound) N-glycans, galactosylation of the α(1-6) arm shifts dramatically its conformational equilibrium from an outstretched to a folded conformation. These findings are in agreement with and can help rationalize recent experimental evidence showing a differential recognition of positional isomers in glycan array data and also the preference of sialyltransferase for the more reachable, outstretched α(1-3) arm in both isolated and Fc-bound N-glycans.
Epigenetic inactivation of miR-203 as a key step in neural crest epithelial-to-mesenchymal transition
Authors: Sánchez-Vásquez Estefanía , Bronner Marianne E. , Strobl-Mazzulla Pablo H.
Published: August 2018

miR-203 is a tumor-suppressor microRNA with known functions in cancer metastasis. Here, we explore its normal developmental role in the context of neural crest development. As neural crest cells undergo an epithelial-to-mesenchymal transition to emigrate from the neural tube, miR-203 displays a reciprocal expression pattern with key regulators of neural crest delamination, Phf12 and Snail2, and interacts with their 3’UTRs. Ectopic maintenance of miR-203 inhibits neural crest migration, whereas its functional inhibition using a “sponge” vector promotes premature neural crest delamination. Bisulfite sequencing further shows that epigenetic repression of miR-203 is mediated by the de novo DNA methyltransferase DNMT3B, whose recruitment to regulatory regions on the miR-203 locus is directed by SNAIL2 in a negative feedback loop. These findings reveal an important role for miR-203 in an epigenetic-microRNA regulatory network that influences the timing of neural crest delamination.

Summary statement

The EMT is a highly conserved process, involving similar levels of regulation in both neural crest and cancer cells. Our work shows an epigenetic-miRNA-gene regulatory circuit, conserved in cancer, which controls the timing of neural crest EMT as well.
Integrative analyses of multi-tissue Hi-C and eQTL data demonstrate close spatial proximity between eQTLs and their target genes
Authors: Yu Jingting , Hu Ming , Li Chun
Published: August 2018

Gene regulation is important for cells and tissues to function. At the genomic level, it has been studied from two aspects, the identification of expression quantitative trait loci (eQTLs) and identification of long-range chromatin interactions. It is important to understand their relationship, such as whether eQTLs regulate their target genes through physical chromatin interaction. Although previous studies have suggested enrichment of eQTLs in regions with a high chromatin interaction frequency, it is unclear whether this relationship is consistent across different tissues and cell lines and whether there would be any tissue-specific patterns. Here, we performed integrative analyses of eQTL and high-throughput chromatin conformation capture (Hi-C) data from 11 human primary tissue types and 2 human cell lines. We found that chromatin interaction frequency is positively correlated with the number of genes having eQTLs, and eQTLs and their target genes are more likely to fall in the same topologically associating domains than that expected from randomly generated control datasets. These results are consistent across all tissues and cell lines we evaluated. Moreover, in dorsolateral prefrontal cortex, spleen, hippocampus, pancreas and aorta, tissue-specific eQTLs are enriched in tissue-specific frequently interacting regions. These results reveal a more detailed picture of the complicated relationship between different mechanisms of gene regulation.

Author summary

Whole-genome gene regulation has been studied in tissues and cell lines from multiple perspectives, including identification of expression quantitative trait loci (eQTLs) and identification of long-range chromatin interactions. These two complementary approaches focus on different aspects of gene regulation, one being statistical across individuals while the other being physical within a sample. Integrating results from these two approaches will help us understand their relationships, such as whether eQTLs regulate their target genes through physical chromatin interaction. We performed comprehensive analyses using data from multiple human tissues and cell lines, and showed that chromatin interaction frequency is positively associated with eQTL results in all evaluated tissues and cell lines. The observed relationships also displayed tissue-specific pattern in some tissues. Our results revealed a more detailed picture of the complicated relationship between the different mechanisms of gene regulation.
Functions of unconventional mammalian translational GTPases GTPBP1 and GTPBP2
Authors: Zinoviev Alexandra , Goyal Akanksha , Jindal Supriya , LaCava John , Komar Anton A. , Rodnina Marina V. , Hellen Christopher U.T. , Pestova Tatyana V.
Published: August 2018

GTP-binding protein 1 (GTPBP1) and GTPBP2 comprise a divergent group of translational GTPases with obscure functions, which are most closely related to eEF1A, eRF3, and Hbs1. Although recent reports implicated GTPBPs in mRNA surveillance and ribosome-associated quality control, how they perform these functions remains unknown. Here, we demonstrate that GTPBP1 possesses eEF1A-like elongation activity, delivering cognate aminoacyl-transfer RNA (aa-tRNA) to the ribosomal A site in a GTP-dependent manner. It also stimulates exosomal degradation of mRNAs in elongation complexes. The kinetics of GTPBP1-mediated elongation argues against its functioning in elongation per se but supports involvement in mRNA surveillance. Thus, GTP hydrolysis by GTPBP1 is not followed by rapid peptide bond formation, suggesting that after hydrolysis, GTPBP1 retains aa-tRNA, delaying its accommodation in the A site. In physiological settings, this would cause ribosome stalling, enabling GTPBP1 to elicit quality control programs; e.g., by recruiting the exosome. GTPBP1 can also deliver deacylated tRNA to the A site, indicating that it might function via interaction with deacylated tRNA, which accumulates during stresses. Although GTPBP2's binding to GTP was stimulated by Phe-tRNAPhe, suggesting that its function might also involve interaction with aa-tRNA, GTPBP2 lacked elongation activity and did not stimulate exosomal degradation, indicating that GTPBP1 and GTPBP2 have different functions.
One way only to synchrotron light sources upgrade?
Authors: Di Mitri Simone
Published: August 2018

The last decade has seen a renaissance of machine-physics studies and technological advancements that aim to upgrade at least 15 synchrotron light sources worldwide to diffraction-limited storage rings. This is expected to improve the average spectral brightness and transversally coherent fraction of photons by several orders of magnitude in the soft- and hard-X-ray wavelength range, at the expense of pulse durations longer than ∼80 ps FWHM. This paper discusses the compatibility of schemes for the generation of sub-picosecond photon-pulse durations in synchrotron light sources with standard multi-bunch user operation and, in particular, diffraction-limited electron optics design. The question of this compatibility is answered taking into consideration the storage ring beam energy and the constraint of existing synchrotrons' infrastructure. An alternative scheme for the upgrade of medium-energy synchrotron light sources to diffraction-limited storage rings and the simultaneous production of picosecond-long photon pulses in a high-gain free-electron laser scheme are illustrated.
In situ study of sigma phase formation in Cr–Co–Ni ternary alloys at 800°C using the long duration experiment facility at Diamond Light Source
Authors: Connor L. D. , Mignanelli P. M. , Christofidou K. A. , Jones N. G. , Baker A. R. , Tang C. C. , Guérin S. , Stone H. J.
Published: August 2018

The new long duration experiment facility on beamline I11 at Diamond Light Source has been used to study the kinetics of sigma phase formation in three Cr–Co–Ni alloys. Diffraction data acquired during in situ exposure at 800°C for 50 d showed progressive increases in the sigma fraction. This was accompanied by changes in the proportions of the other phases, which differed markedly between the alloys studied. These results demonstrate the capabilities of the long duration facility for the study of metallurgical phenomena over periods of months to years, a capability not previously available at a synchrotron source.
High-efficiency coherence-preserving harmonic rejection with crystal optics
Authors: Zhang Fan , Allen Andrew J. , Levine Lyle E. , Long Gabrielle G. , Kuzmenko Ivan , Ilavsky Jan
Published: August 2018

This work reports a harmonic-rejection scheme based on the combination of Si(111) monochromator and Si(220) harmonic-rejection crystal optics. This approach is of importance to a wide range of X-ray applications in all three major branches of modern X-ray science (scattering, spectroscopy, imaging) based at major facilities, and especially relevant to the capabilities offered by the new diffraction-limited storage rings. It was demonstrated both theoretically and experimentally that, when used with a synchrotron undulator source over a broad range of X-ray energies of interest, the harmonic-rejection crystals transmit the incident harmonic X-rays on the order of 10−6. Considering the flux ratio of fundamental and harmonic X-rays in the incident beam, this scheme achieves a total flux ratio of harmonic radiation to fundamental radiation on the order of 10−10. The spatial coherence of the undulator beam is preserved in the transmitted fundamental radiation while the harmonic radiation is suppressed, making this scheme suitable not only for current third-generation synchrotron sources but also for the new diffraction-limited storage rings where coherence preservation is an even higher priority. Compared with conventional harmonic-rejection mirrors, where coherence is poorly preserved and harmonic rejection is less effective, this scheme has the added advantage of lower cost and footprint. This approach has been successfully utilized at the ultra-small-angle X-ray scattering instrument at the Advanced Photon Source for scattering, imaging and coherent X-ray photon correlation spectroscopy experiments. With minor modification, the harmonic rejection can be improved by a further five orders of magnitude, enabling even more performance capabilities.
Institutional pressures, isomorphic changes and key agents in the transfer of knowledge of Lean in Healthcare
Authors: D’Andreamatteo Antonio , Ianni Luca , Rangone Adalberto , Paolone Francesco , Sargiacomo Massimo
Published: August 2018

Purpose

Application of operations management in healthcare is particularly promising to improve the overall organisational performance, although the Italian system is behind in introducing related techniques and methods. One of the recent experiments in healthcare is the implementation of “Lean Thinking”. The purpose of this paper is to investigate which exogenous forces are driving knowledge transfer on Lean, both in the private and public healthcare sectors.

Design/methodology/approach

Informed by institutional sociology (DiMaggio and Powell, 1983; Powell and DiMaggio, 1991), the paper builds on the case study methodology (Yin, 2013) to elucidate the environmental pressures that are encouraging the adoption of Lean thinking by Italian hospitals and Local Health Authorities.

Findings

The study highlights the economic, coercive, mimetic and normative pressures that are triggering the adoption of Lean thinking in the Italian National Health System (INHS). At the same time, the authors reveal the pivotal importance and innovative roles played by diverse prominent key-actors in the different organisations investigated.

Originality/value

Considering that little is known to date regarding which exogenous forces are driving the transfer of knowledge on Lean, especially in the public healthcare sector, the paper allows scholars to focus on patterns of isomorphic change and will facilitate managers and policy makers to understand exogenous factors stimulating the transfer of Lean thinking and the subsequent innovation within health organisations and systems.
When queen bees attack women stop advancing: recognising and addressing female bullying in the workplace
Authors: Harvey Cecila
Published: August 2018

Purpose

This paper aims to look at the implications of the “Queen Bee” syndrome in the workplace: its impact on women at work and the perception of women at work.

Design/methodology/approach

This paper draws on the author’s practical experience, observations, and studies.

Findings

The Queen Bee syndrome can have a negative impact on organizational performance and bottom-line results as well as individuals.

Research limitations/implications

The author calls for more work to done in this area to raise awareness and provide solutions.

Practical implications

This paper offers insight to help managers and organizations assess how much the Queen Bee syndrome may be at work in their own organization. It also invites women to self-reflect on their own behaviors.

Originality/value

This paper highlights an issue that can be ignored in organizations – how negative woman-to-woman behavior and/or bullying can be detrimental to individual and organizational performance.
Internationalization as a determinant of systematic risk: the role of restaurant type
Authors: Jung SoYeon , Dalbor Michael , Lee Seoki
Published: August 2018

Purpose

The purpose of this study is twofold: to investigate the relationship between restaurant firms’ internationalization and systematic risk, and to further examine the relationship between internationalization and systematic risk based on the type of restaurant firm (i.e. limited-service vs full-service restaurants).

Design/methodology/approach

This study analyzes data from US-based publicly traded restaurant firms by estimating systematic risk based on the Carhart four-factor model and by performing a two-way random-effects model.

Findings

Findings support not only the risk-reduction effect of internationalization on systematic risk but also the moderating effect of the role of restaurant type on the relationship between internationalization and systematic risk. More specifically, the risk-reduction effect of internationalization on systematic risk is greater for limited-service than full-service restaurants.

Practical implications

The findings of this study can provide restaurant executives with more confidence in pursuing internationalization as part of their risk management strategy, acknowledging that more international operations could mitigate restaurant firms’ systematic risk. More specifically, limited-service restaurants can more significantly enjoy the risk-reduction benefits by increasing their international operations than full-service restaurants based on the findings of this study. Furthermore, risk-averse investors could consider purchasing shares of limited-service multinational restaurants’ stocks to enjoy more risk-reduction benefits.

Originality/value

By focusing on the restaurant industry with consideration for the restaurant type, this study provides more tailored recommendations for implementing internationalization strategies with regard to risk management.