bluuebunny/crossref_metadata_2025 huggingface dataset:
The (p)ppGpp-binding GTPase Era promotes rRNA processing and cold adaptation in Staphylococcus aureus
Authors: Wood Alison , Irving Sophie , Bennison Daniel , Corrigan Rebecca
Published: January 2020

Ribosome assembly cofactors are widely conserved across all domains of life. One such group, the ribosome-associated GTPases (RA-GTPase), act as molecular switches to coordinate ribosome assembly. We previously identified the Staphylococcus aureus RA-GTPase Era as a target for the stringent response alarmone (p)ppGpp, with binding leading to inhibition of GTPase activity. Era is highly conserved throughout the bacterial kingdom and is essential in many species, although the function of Era in ribosome assembly is unclear. Here we show that Era is not essential in S. aureus but is important for 30S ribosomal subunit assembly. Protein interaction studies reveal that Era interacts with the 16S rRNA endonuclease YbeY and the DEAD-box RNA helicase CshA. We determine that both Era and CshA are required for growth at suboptimal temperatures and rRNA processing. Era and CshA also form direct interactions with the (p)ppGpp synthetase Rel
Sau
, with Rel
Sau
positively impacting the GTPase activity of Era but negatively affecting the helicase activity of CshA. We propose that in its GTP-bound form, Era acts as a hub protein on the ribosome to direct enzymes involved in rRNA processing/degradation and ribosome subunit assembly to their site of action. This activity is impeded by multiple components of the stringent response, contributing to the slowed growth phenotype synonymous with this stress response pathway.
Significance of the chromosomal positions of the genes encoding DNA gyrase in Salmonella enterica Serovar Typhimurium
Authors: Pozdeev German
Published: January 2020

Changing positions of genes on a chromosome is an informative way of learning about why an existing chromosome structure and gene order was selected by evolution in bacteria. In Salmonella gyrA and gyrB – genes encoding DNA gyrase – enzyme that introduces negative supercoils in DNA, are located almost at opposite poles of a chromosome. However, in many other bacteria they are arranged in a gyrBA operon. In order to investigate the significance of this fact, gyrBA operon was made in Salmonella by bringing gyrA open reading frame and its ribosome binding site directly downstream of gyrB and under a control of its regulatory regions, the original copy of gyrA was deleted. The gyrBA strain obtained as a result exhibits no differences from the wild type in growth and morphology, however, the ability to supercoil DNA is altered between gyrBA and the WT. This is specifically important at conditions mimicking environment inside a macrophage in terms of Mg2+ concentration, as it may suggest alteration of gyrBA survival inside a macrophage. An attempt to make strain with gyrAB operon was not successful, as it was not possible to delete the original gyrB, suggesting particular importance of its position.
The evolution of Pseudomonas aeruginosa during short-term acute respiratory infections
Authors: Wheatley Rachel , Kapel Natalia , Caballero Julio Diaz , Paling Fleur , Sifakis Frangiscos , Ruzin Alexey , Timbermont Leen , Kluytmans Jan , Malhotra Surbhi , MacLean Craig
Published: January 2020

Background. The emergence and spread of bacteria with resistance to multiple antimicrobial agents is raising the mortality rates associated with bacterial infections, and poses a fundamental threat to human health. Pseudomonas aeruginosais an opportunistic human pathogen that is responsible for 10-15% of health-care associated infections worldwide, and is known for its ability to rapidly develop enhanced resistance during the course of treating an infection.

Methods.
P. aeruginosa isolates have been collected from ICU patients in hospitals across Europe over a longitudinal sampling of short-term acute respiratory infection. Twelve isolates per patient per sampling of infection have been acquired. Genome sequencing and high-throughput phenotyping of growth rate and antibiotic resistance profile has been carried out.

Results and conclusions. Using high-throughput phenotyping and genome sequence data we have been able to characterise population diversity and variation in phenotypic resistance profile, growth rate and acquired resistance gene content of these isolates. A gradient of diversity was found within patient infections, ranging from monoclonal to multiple strains present. Large within-patient population diversity in phenotypic resistance profile and acquired resistance gene content could be observed in multiple sequence-type infections.

This research has been carried out in collaboration with the COMBACTE-MAGNET research consortium (Combatting Bacterial Resistance in Europe – Molecules against Gram-Negative Infections).
A matter of life and death; identifying host genomic factors that determine susceptibility of chickens to highly pathogenic avian influenza
Authors: Donnelly Cal , Fulton Janet E. , Wolc Anna , Drobik-Czwarno Wioleta , Digard Paul , Smith Jacqueline
Published: January 2020

DNA samples collected from survivors of recent outbreaks of highly pathogenic avian influenza (HPAI) in Mexico and the USA have provided a rare opportunity to study the genetic mechanisms underpinning susceptibility of chickens to this devastating and economically impactful disease which normally exhibits 70-100% mortality in the chicken host. Whole Genome Sequence (WGS) data has been used to perform Genome-Wide Association Studies (GWAS), which have highlighted single nucleotide polymorphisms (SNPs) segregating significantly between survivors and controls, with a pedigreed experimental group exhibiting a highly significant signal on chicken chromosome 2 in the region of a biologically relevant gene. Candidate SNPs for resilience are currently being validated using in vitro gene editing methodologiesthat modulate candidate gene expression to investigate the effect on viral replication and cellular response to HPAI infection. A detailed understanding of the genomic resilience to HPAI from this study will have implications for both the poultry industry and for public health.
Characterising the urinary microbial community in patients with symptoms of urinary tract infection
Authors: Sathiananthamoorthy Sanchutha , Malone-Lee James , Spratt David , Rohn Jennifer
Published: January 2020

Background. Every year 250 million individuals develop urinary tract infections (UTI), the diagnosis of which, usually involves the ‘gold standard’ midstream urine culture (MSU) test. Prompt detection aided by sensitive tests may increase the likelihood of successful treatment. However, recent evidence highlights the potential inadequacies of this test.

Methods. We assessed the UK’s MSU culture by comparison with enhanced culture techniques and 16S rRNA gene sequencing. With ethical approval, patients attending their first consultation at the Whittington Hospital Clinic and asymptomatic controls provided MSU specimens. Each specimen was submitted to the Hospital Microbiology laboratory for MSU culture. 16S rRNA gene sequencing was performed on 1ml unspun urine and 30ml of centrifuged urine.

Results. Urine specimens were analysed for 33 patients (mean age= 49 years, sd=16.5) and 29 controls (mean age=40.7 years, sd=15.7). Comparison of routine MSU cultures between patients and controls indicated that the test failed to discriminate between patients and controls(χ2= 0.539, df = 1, P = 0.674).Bacterial DNA was detected in 97.0% patients and 89.7% controls. Enterobacteriaceae was most abundant in patients, whereas Streptococcus dominated in controls. A higher distribution of the median number of observed taxa (centrifuged and unspun samples combined) was seen in patients (χ2 = 8.0, df = 2, P <0.05).

Conclusion. The MSU culture failed to discriminate between patients and controls and missed recognised uropathogens that were detected with bacterial DNA sequencing. Microbial communities characterised by sequencing warrant further investigation to understand the role of each member in UTI.
Development of a microbially-derived therapy against Fusobacterium nucleatum, a bacterial pathogen linked with colorectal cancer
Authors: Lawrence Garreth , McCarthy Niamh , Begley Máire , Cotter Paul , Guinane Caitriona
Published: January 2020

Background. Specific bacterial species have been linked to several intestinal diseases, including colorectal cancer (CRC). In recent years, high abundances of an emerging pathogen, Fusobacterium nucleatum, have been identified in tumors and stool samples of CRC patients and it has been suggested that F. nucleatum contributes to CRC initiation and development. The possibility of suppressing the growth of F. nucleatum in the GI tract using antimicrobial-producing probiotic bacteria may reduce the overall risk of CRC development.

Methods. Here, we screen a collection of faecal samples from healthy donors against F. nucleatum in an effort to discover an antimicrobial-producing isolate capable of selectively inhibiting this emerging human pathogen. Potential isolates with anti-Fusobacterial activity were then further analysed for the ability to inhibit the pathogen in cell culture and in a faecal fermentation system, which simulates the dynamic conditions of the human colon.

Results. Culture-based screening of over 16,000 colonies of gastrointestinal origin resulted in the identification of one faecal isolate with probiotic potential displaying significant antagonistic activity against F. nucleatum initially in cell culture media and subsequently inhibition was confirmed in the simulated intestinal model.

Conclusion. This study reveals that, a novel gut isolate demonstrates inhibition against the CRC-associated F. nucleatum in vitro and suppresses its growth in a model of the human distal colon. This is an important finding, suggesting the potential of a natural gut bacterium to supress the growth of a bacterial pathogen associated with CRC, which may contribute to reducing the overall risk of developing the disease.
Quorum quenching activity of Aerva lanata against Catheter Associated Urinary Tract Infections (CAUTI) Pathogens
Authors: Mohanvel Sucharitha Kannappan , Rajasekharan Satish Kumar
Published: January 2020

Background. CAUTI is the most common hospital infection caused by Gram-negative bacterium owing to their ability to colonize UT mucosa. These uro-pathogens elaborate quorum sensing (QS) molecules that modify the expression and secretion of biofilm matrix compounds in response to rheological and other UT changes during catheterization. Quenching the biological effects of QS molecules will have substantial clinical value. This study identifies and evaluate the antibiofilm/anti-virulence properties of Aerva lanata plant extract against select CAUTI pathogens.

Methods. Methanolic extract of Aerva lanata was screened for its anti-urobacterial effects using Chromobacterium violaceum as the test strain. A. lanata extract impact on the QS molecule, acyl homoserine lactone (AHL) regulated bacterial functions essential for biofilm formation was investigated. It includes RT-PCR analysis of QS genes in the bacterium and in silico studies of bacterial compounds.

Results. Methanolic extract of A. lanata interfered with AHL regulated physiological functions such as biofilm formation, pellicle inhibition, flagellar motility and exopolysaccharides (EPS) production. In situ-visualization of biofilm with confocal microscopy showed concentration influenced reduction in bacterial biofilm formation in response to plant extract. GC-MS identified 11 compounds and molecular docking analysis predicted their respective host receptors. In silico analysis of plant extract revealed putative compounds with potential to inhibit the bacterial QS AHL system. RT-PCR analysis revealed down regulation of QS related virulence genes viz., las1, lasR, lasB, lasA.

Conclusion. Data obtained in this study strongly suggests that Aerva lanata should be further investigated for its therapeutic potentials to treat bacterial CAUTI.
Lactate improves killing of Mycobacterium tuberculosis in human macrophages
Authors: Maoldomhnaigh Cilian Ó , Cox Donal , McQuaid Kate , Gogan Karl , Basdeo Sharee , Keane Joseph
Published: January 2020

Mycobaterium tuberculosis (Mtb) kills more people than any other infectious agent worldwide. Our group has shown the importance of glycolysis in controlling intracellular Mtb growth in human macrophages1, which leads to increased lactate production. Therefore, we examined if lactate had an immunomodulatory effect on human monocyte derived macrophages (hMDM) infected with Mtb.

hMDM were adherence purified from healthy donor buffy coats with human serum for 6-8 days. Sodium L-Lactate was added 3 hours prior to infection with Mtb or stimulation with LPS (100 ng/ml). Macrophage phenotype and function was assessed by ELISA, flow cytometry and Seahorse metabolic-flux analysis. Bacillary killing was determined by colony forming units (CFU) after lysing infected hMDM, plating on middlebrook agar and counting 21 days later.

25 mM of lactate improves hMDM ability to control intracellular Mtb growth with a 55% reduction in CFU at day 5 post infection. The glycolytic response seen immediately following infection with Mtb or LPS stimulation was decreased with lactate. LPS-induced upregulation of activation markers was diminished by lactate.

Lactate is a product of aerobic glycolysis induced by infection and supports the intracellular killing of Mtb. Further research is required to elucidate the mechanism of this effect.

1. Gleeson, L. E. et al. Cutting Edge: Mycobacterium tuberculosis Induces Aerobic Glycolysis in Human Alveolar Macrophages That Is Required for Control of Intracellular Bacillary Replication. J. Immunol. 196, 2444–2449 (2016).
The molecular basis of antibiotic treatment failure in chronic urinary tract infections
Authors: Fatti Claudio Del , Jafari Nazila , Hubbard Alasdair , Khasriya Rajvinder , Roberts Adam , Rohn Jennifer
Published: January 2020

Urinary tract infections (UTIs) are amongst the most common infections worldwide, and are becoming increasingly difficult to treat. In addition to the acceleration of classic antimicrobial resistance, recurrence after initial resolution is common. Our clinical experience is that chronically infected patients sometimes fail to respond to antibiotics predicted to be effective from culture-based sensitivity testing, while antibiotics predicted to be unsuitable can succeed. We hypothesized that the bladder environment could lead to differential bacterial gene expression, resulting in differences in minimum inhibitory concentration (MICs) compared with standard culture.

Here, using strains of Escherichia coli evolved in the lab to be resistant to amoxicillin–clavulanic acid, we present data that MICs differ depending on which media the assay is performed in (M9, ISO, LB, human urine), as well as in urine-containing supernatant enriched from urothelial organoids. Next, we examined the behaviour of patient-derived Enterococcus faecalis, one of the main causative agents of chronic UTIs in the elderly. We are in the process of evaluating the MIC of first-line UTI antibiotics using growth media supplemented with urine, to more closely mimic the native uropathogen environment. Moreover, we are characterising the resistance genes expressed in those differing environments using next generation sequencing technology and comparing the results with those obtained from bacteria grown on standard diagnostic media.

Our work demonstrates the danger of extrapolating biological behaviour from artificial culture substrates and may lead to better diagnostic tests and treatments for chronic UTI.
Socially messaging polycellular interactomes for innovative interventions in health and medicine
Authors: Reen F. Jerry
Published: January 2020

The fast approaching post-antibiotic era has focused efforts on the search for new classes of antimicrobial compounds to arrest the increase in mortality levels attributed to microbial infections. Key to this has been the realisation that persistent infections arise from changes in polymicrobial communities, and the interactions between the protagonists within these communities can markedly affect the effectiveness of antibiotic-based interventions. Understanding the impact of key interactions within these ecosystems is key to priming the effectiveness of drug-based interventions.

We are pursuing a chemico-biological approach to investigate the molecular mechanisms underlying the anti-infective activity of small molecules from microbe-host interactomes. Evolved through co-existence, these novel molecular entities offer an effective means of pathogen control through a form of ‘chemical messaging’. Accessing the thesaurus of microbial messaging through rational design has led to a suite of distinct bioactive frameworks that can influence inter-species behaviours, moderating chronic and acute phases of virulence and pathogenesis in Pseudomonas aeruginosa and other pathogens. Similarly, at the interkingdom level, small molecular entities with anti-inflammatory and anti-cancer activities have been identified. Elucidating the molecular mechanisms underpinning the bioactive potential of these small molecules is key to unlocking their potential to deliver next generation medicines. This can only be done with a deeper understanding of the pathoadaptive phenotypic and genotypic heterogeneity that is emerging from clinical studies.
VarFish - Collaborative and Comprehensive Variant Analysis for Diagnosis and Research
Authors: Holtgrewe Manuel , Stolpe Oliver , Nieminen Mikko , Mundlos Stefan , Knaus Alexej , Kornak Uwe , Seelow Dominik , Segebrecht Lara , Spielmann Malte , Fischer-Zirnsak Björn , Boschann Felix , Scholl Ute , Ehmke Nadja , Beule Dieter
Published: January 2020

VarFish is a user-friendly web application for the quality control, filtering, prioritization, analysis, and user-based annotation of panel and exome variant data for rare disease genetics. It is capable of processing variant call files with single or multiple samples. The variants are automatically annotated with population frequencies, molecular impact, and presence in databases such as ClinVar. Further, it provides support for pathogenicity scores including CADD, MutationTaster, and phenotypic similarity scores. Users can filter variants based on these annotations and presumed inheritance pattern and sort the results by these scores. Filtered variants are listed with their annotations and many useful link-outs to genome browsers, other gene/variant data portals, and external tools for variant assessment. VarFish allows user to create their own annotations including support for variant assessment following ACMG-AMP guidelines. In close collaboration with medical practitioners, VarFish was designed for variant analysis and prioritization in diagnostic and research settings as described in the software’s extensive manual. The user interface has been optimized for supporting these protocols. Users can install VarFish on their own in-house servers where it provides additional lab notebook features for collaborative analysis and allows re-analysis of cases, e.g., after update of genotype or phenotype databases.
Interpretable detection of novel human viruses from genome sequencing data
Authors: Bartoszewicz Jakub M. , Seidel Anja , Renard Bernhard Y.
Published: January 2020

Viruses evolve extremely quickly, so reliable methods for viral host prediction are necessary to safeguard biosecurity and biosafety alike. Novel human-infecting viruses are difficult to detect with standard bioinformatics workflows. Here, we predict whether a virus can infect humans directly from next-generation sequencing reads. We show that deep neural architectures significantly outperform both shallow machine learning and standard, homology-based algorithms, cutting the error rates in half and generalizing to taxonomic units distant from those presented during training. Further, we develop a suite of interpretability tools and show that it can be applied also to other models beyond the host prediction task. We propose a new approach for convolutional filter visualization to disentangle the information content of each nucleotide from its contribution to the final classification decision. Nucleotide-resolution maps of the learned associations between pathogen genomes and the infectious phenotype can be used to detect regions of interest in novel agents, for example the SARS-CoV-2 coronavirus, unknown before it caused a COVID-19 pandemic in 2020. All methods presented here are implemented as easy-to-install packages enabling analysis of NGS datasets without requiring any deep learning skills, but also allowing advanced users to easily train and explain new models for genomics.
dnmt1function is required to maintain retinal stem cells within the ciliary marginal zone of the zebrafish eye
Authors: Angileri Krista M. , Gross Jeffrey M.
Published: January 2020

The ciliary marginal zone (CMZ) of the zebrafish retina contains a population of actively proliferating resident stem cells, which generate retinal neurons throughout life. The maintenance methyltransferase,dnmt1, is expressed within the CMZ. Loss of dnmt1 function results in gene misregulation and cell death in a variety of developmental contexts, however, its role in retinal stem cell (RSC) maintenance is currently unknown. Here, we demonstrate that zebrafishdnmt1s872mutants possess severe defects in RSC maintenance within the CMZ. Using a combination of immunohistochemistry,in situhybridization, and a transgenic reporter assay, our results demonstrate a requirement for dnmt1 activity in the regulation of RSC proliferation, gene expression and in the repression of endogenous retroelements (REs). Ultimately, cell death is elevated in thednmt1-/-CMZ, but in ap53-independent manner. Using a transgenic reporter for RE transposition activity, we demonstrate increased transposition in thednmt1-/-CMZ. Taken together our data identify a critical role for dnmt1 function in RSC maintenance in the vertebrate eye.
Insights into Cross-species Evolution of Novel Human Coronavirus SARS-CoV-2 and Defining Immune Determinants for Vaccine Development
Authors: Ramaiah Arunachalam , Arumugaswami Vaithilingaraja
Published: January 2020

Novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak in the city of Wuhan, China during December 2019, has now spread to various countries across the globe triggering a heightened containment effort. This human pathogen is a member of betacoronavirus genus carrying 30 kilobase of single positive-sense RNA genome. Understanding the evolution, zoonotic transmission, and source of this novel virus would help accelerating containment and prevention efforts. The present study reported detailed analysis of SARS-CoV-2 genome evolution and potential candidate peptides for vaccine development. This new coronavirus genotype might have been evolved from a bat-coronavirus by accumulating non-synonymous mutations, indels, and recombination events. Structural proteins Spike (S), and Membrane (M) had extensive mutational changes, whereas Envelope (E) and Nucleocapsid (N) proteins were very conserved suggesting differential selection pressures exerted on SARS-CoV-2 during evolution. Interestingly, SARS-CoV-2 Spike protein contains a 39 nucleotide sequence insertion relative to SARS-like bat-SL-CoVZC45/2017. Furthermore, we identified eight high binding affinity (HBA) CD4 T-cell epitopes in the S, E, M and N proteins, which can be commonly recognized by HLA-DR alleles of Asia and Asia-Pacific Region population. These immunodominant epitopes can be incorporated in universal subunit SARS-CoV-2 vaccine. Diverse HLA types and variations in the epitope binding affinity may contribute to the wide range of immunopathological outcomes of circulating virus in humans. Our findings emphasize the requirement for continuous surveillance of SARS-CoV-2 strains in live animal markets to better understand the viral adaptation to human host and to develop practical solutions to prevent the emergence of novel pathogenic SARS-CoV-2 strains.
The crystal structure of the TonB-dependent transporter YncD reveals a positively charged substrate binding site
Authors: Grinter Rhys , Lithgow Trevor
Published: January 2020

The outer membrane of Gram-negative bacteria is highly impermeable to hydrophilic molecules larger than 600 Da, protecting these bacteria from toxins present in the environment. In order to transport nutrients across this impermeable membrane, Gram-negative bacteria utilise a diverse family of outer-membrane proteins called TonB-dependent transporters. The majority of this family transport iron-containing substrates. However, it is becoming increasingly clear that TonB-dependent transporters target chemically diverse substrates. In this work, we investigate the structure and phylogenetic distribution of the TonB-dependent transporter YncD. We show that while YncD is present in some enteropathogens includingE. coliandSalmonellaspp., it is also widespread in Gamma and Betaproteobacteria of environmental origin. We determine the structure of YncD, showing that despite a distant evolutionary relationship, it shares structural features with the ferriccitrate transporter FecA, including a compact positively-charged substrate-binding site. Despite these shared features, we show that YncD does not contribute to the growth ofE. coliin pure culture under-iron limiting conditions or with ferric-citrate as an iron source. Previous studies on transcriptional regulation inE. colishow that YncD is not induced under iron-limiting conditions and is unresponsive to the Ferric uptake regulator (Fur). These observations combined with the data we present, suggest that YncD is not responsible for the transport of an iron-containing substrate.
The genetic structure and adaptation of Andean highlanders and Amazonian dwellers is influenced by the interplay between geography and culture
Authors: Borda Victor , Alvim Isabela , Aquino Marla M , Silva Carolina , Soares-Souza Giordano B , Leal Thiago P , Scliar Marilia O , Zamudio Roxana , Zolini Camila , Padilla Carlos , Cáceres Omar , Levano Kelly , Sanchez Cesar , Trujillo Omar , Flores-Villanueva Pedro O. , Dean Michael , Fuselli Silvia , Machado Moara , Romero Pedro E. , Tassi Francesca , Yeager Meredith , O’Connor Timothy D. , Gilman Robert H , Tarazona-Santos Eduardo , Guio Heinner
Published: January 2020

Western South America was one of the worldwide cradles of civilization. The well known Inca Empire was thetip of the icebergof a cultural and biological evolutionary process that started 14-11 thousand years ago. Genetic data from 18 Peruvian populations reveal that: (1) The between-population homogenization of the central-southern Andes and its differentiation with respect to Amazonian populations of similar latitudes do not extend northward. Instead, longitudinal gene flow between the northern coast of Peru, Andes and Amazonia accompanied cultural and socioeconomic interactions revealed by archeological studies. This pattern recapitulates the environmental and cultural differentiation between the fertile north, where altitudes are lower; and the arid south, where the Andes are higher, acting as a genetic barrier between the sharply different environments of the Andes and Amazonia (2). The genetic homogenization between the populations of the arid Andes is not only due to migration during the Inca Empire or the subsequent colonial period. It started at least during the earlier expansion of the pre-Inca Wari Empire (600-1000 YBP) (3) This demographic history allowed for cases of positive natural selection in the high and arid Andes vs. the low Amazon tropical forest: in the Andes,HAND2-AS1(heart and neural crest derivatives expressed 2 antisense RNA1, related with cardiovascular function) andDUOX2(dual oxidase 2, related to thyroid function and innate immunity) genes; in the Amazon, the gene encoding for the CD45 protein, essential for antigen recognition by T/B lymphocytes in viral-host interaction, consistent with thehost-virus arms racehypothesis.
Identification of Relevant Genetic Alterations in Cancer using Topological Data Analysis
Authors: Rabadán Raúl , Mohamedi Yamina , Rubin Udi , Chu Tim , Elliott Oliver , Arnés Luis , Cal Santiago , Obaya Álvaro J. , Levine Arnold J. , Cámara Pablo G.
Published: January 2020

Large-scale cancer genomic studies enable the systematic identification of mutations that lead to the genesis and progression of tumors, uncovering the underlying molecular mechanisms and potential therapies. While some such mutations are recurrently found in many tumors, many others exist solely within a few samples, precluding detection by conventional recurrence-based statistical approaches. Integrated analysis of somatic mutations and RNA expression data across 12 tumor types reveals that mutations of cancer genes are usually accompanied by substantial changes in expression. We use topological data analysis to leverage this observation and uncover 38 elusive candidate cancer-associated genes, including inactivating mutations of the metalloproteinase ADAMTS12 in lung adenocarcinoma. We show thatADAMTS12−/−mice have a five-fold increase in the susceptibility to develop lung tumors, confirming the role ofADAMTS12as a tumor suppressor gene. Our results demonstrate that data integration through topological techniques can increase our ability to identify previously unreported cancer-related alterations.
MAGGIE: leveraging genetic variation to identify DNA sequence motifs mediating transcription factor binding and function
Authors: Shen Zeyang , Hoeksema Marten A , Ouyang Zhengyu , Benner Christopher , Glass Christopher K
Published: January 2020

Genetic variation in regulatory elements can alter transcription factor (TF) binding by mutating a TF binding motif, which in turn may affect the activity of the regulatory elements. However, it is unclear which TFs are prone to be affected by a given variant. Current motif analysis tools either prioritize TFs based on motif enrichment without linking to a function or are limited in their applications due to the assumption of linearity between motifs and their functional effects. Here, we present MAGGIE, a novel method for identifying motifs mediating TF binding and function. By leveraging measurements from diverse genotypes, MAGGIE uses a statistical approach to link mutation of a motif to changes of an epigenomic feature without assuming a linear relationship. We benchmark MAGGIE across various applications using both simulated and biological datasets and demonstrate its improvement in sensitivity and specificity compared to the state-of-the-art motif analysis approaches. We use MAGGIE to reveal insights into the divergent functions of distinct NF-κB factors in the pro-inflammatory macrophages, showing its promise in discovering novel functions of TFs. The Python package for MAGGIE is freely available athttps://github.com/zeyang-shen/maggie.
Combined impact of pesticides and other environmental stressors on taxonomic richness of freshwater animals in irrigation ponds
Authors: Ito Hiroshi C. , Shiraishi Hiroaki , Nakagawa Megumi , Takamura Noriko
Published: January 2020

Rice paddy irrigation ponds can sustain surprisingly high taxonomic richness and make significant contributions to regional biodiversity. We evaluated the impacts of pesticides and other environmental stressors on the taxonomic richness of freshwater animals in 21 irrigation ponds in Japan. We sampled a wide range of freshwater animals (reptiles, amphibians, fishes, mollusks, crustaceans, insects, annelids, bryozoans, and sponges) and surveyed environmental variables related to pesticide contamination, eutrophication, decreased macrophyte coverage, physical habitat destruction, and invasive alien species. Statistical analyses comprised contraction of highly correlated environmental variables, best-subset model selection, stepwise model selection, and permutation tests. Results showed that: (i) probenazole (fungicide) was the unique significant stressor on fish (i.e., contamination with this compound had a significantly negative correlation with fish taxonomic richness), (ii) the interaction of BPMC (insecticide; also known as fenobucarb) and bluegill (invasive alien fish) was a significant stressor on a “large insect” category (Coleoptera, Ephemeroptera, Hemiptera, Lepidoptera, Odonata, and Trichoptera), (iii) the interaction of BPMC and concrete bank was a significant stressor on an “invertebrate” category, (iv) the combined impacts of BPMC and the other stressors on the invertebrate and large insect categories resulted in an estimated mean loss of taxonomic richness by 15% and 77%, respectively, in comparison with a hypothetical pond with preferable conditions.
Modelling the combined effects of hydrogen traps and surface films on hydrogen permeation in ferritic steels
Authors: Zhi Huihui , Yu Haiyang , Gao Lei , Zhang Zhiliang , Su Yanjing
Published: January 2020

Purpose

The purpose of this study is to develop a model extending Oriani’s formula by introducing a normalised concentration to simulate hydrogen diffusion in a multi-material system such as coated steels, under the presence of traps.

Design/methodology/approach

Implemented through the finite element method based on the analogy between mass diffusion and heat transfer, the governing equation was applied to investigate the combined effects of hydrogen traps and surface oxide films on hydrogen permeation in ferritic steels.

Findings

This study shows that the effective diffusivity varies over several orders of magnitude depending on the traps and films. This explains the divergence of measured hydrogen diffusivities in steels. It is revealed that hydrogen permeation in steels with Pd or Ni film is a trapping-dominant transport process, while hydrogen permeation in steel with oxide film is a process controlled by both trapping effect and retarding effect of oxide film. The oxide film enhances total hydrogen concentration within the steel substrate and is therefore detrimental. The Pd or Ni film has a little influence on total hydrogen concentration distribution depending on trapping energy.

Originality/value

Hydrogen flux curves and transient hydrogen concentration distributions can be directly obtained through the developed model. The proposed approach can also be extended to investigate other interstitial (i.e. carbon, oxygen and nitrogen) diffusion with traps revisited in complex systems.
Multidisciplinary design optimization using knowledge management applied to an electronic throttle
Authors: Mcharek Mehdi , Azib Toufik , Hammadi Moncef , Larouci Cherif , Choley Jean-Yves
Published: January 2020

Purpose

Within the current industrial context, companies aim to decrease the design process time and cost. The multidisciplinary design optimization (MDO) appears as a solution to accelerate the process and support designers in different stages of the design cycle. However, this relatively new concept needs to be integrated efficiently in the industrial environment and issues related to collaboration, data management, traceability and reuse need to be overcome.

Design/methodology/approach

The aim of this work is to efficiently integrate the MDO in the industrial design cycle by means of knowledge management (KM) techniques. To take into account the industrial environment, the methodology was applied in a collaborative software.

Findings

An example of collaborative design and optimization of an electronic throttle body (ETB) controller is presented with industrial requirements. The design problem was solved successfully and demonstrates the efficiency of the methodology in collaborative environments.

Originality/value

The contributions of this work lie in the structuration of the knowledge to support MDO and the definition of a general way to connect the existent MDO tools to the knowledge base. This methodology will enable to freely link different steps of the design process and reduce considerably the setting time of MDO in industries.
Stochastic investigation of graphene structures with efficient polynomial models
Authors: Zygiridis Theodoros , Amanatiadis Stamatis A. , Karamanos Theodosios , Kantartzis Nikolaos V.
Published: January 2020

Purpose

The extraordinary properties of graphene render it ideal for diverse contemporary and future applications. Aiming at the investigation of certain aspects commonly overlooked in pertinent works, the authors study wave-propagation phenomena supported by graphene layers within a stochastic framework, i.e. when uncertainty in various factors affects the graphene’s surface conductivity. Given that the consideration of an increasing number of graphene sheets may increase the stochastic dimensionality of the corresponding problem, efficient surrogates with reasonable computational cost need to be developed.

Design/methodology/approach

The authors exploit the potential of generalized Polynomial Chaos (PC) expansions and develop low-cost surrogates that enable the efficient extraction of the necessary statistical properties displayed by stochastic graphene-related quantities of interest (QoI). A key step is the incorporation of an initial variance estimation, which unveils the significance of each input parameter and facilitates the selection of the most appropriate basis functions, by favoring anisotropic formulae. In addition, the impact of controlling the allowable input interactions in the expansion terms is investigated, aiming at further PC-basis elimination.

Findings

The proposed stochastic methodology is assessed via comparisons with reference Monte-Carlo results, and the developed reduced basis models are shown to be sufficiently reliable, being at the same time computationally cheaper than standard PC expansions. In this context, different graphene configurations with varying numbers of random inputs are modeled, and interesting conclusions are drawn regarding their stochastic responses.

Originality/value

The statistical properties of surface-plasmon polaritons and other QoIs are predicted reliably in diverse graphene configurations, when the surface conductivity displays non-trivial uncertainty levels. The suggested PC methodology features simple implementation and low complexity, yet its performance is not compromised, compared to other standard approaches, and it is shown to be capable of delivering valid results.
Critical success factors of the continued usage of digital library successful implementation in military-context
Authors: Abdul Rahman Abdul Rahim , Mohezar Suhana , Habidin Nurul Fadly , Mohd Fuzi Nursyazwani
Published: January 2020

Purpose

This paper aims to identify the critical success factors of the continued usage of digital library (DL) successful implementation from the perspective of users with organisation support factors as key antecedents.

Design/methodology/approach

Based on the extensive literature review, this study has constructed a conceptual framework based on organisational support perspectives and updated Delone and McLean’s information system success model. A pilot study was carried out on a sample of 105 respondents from military-context. A survey instrument including 22 measurement items was designed to identify the level of DL information system (IS) successful implementation practices in military context. Descriptive statistical analysis and reliability analysis were used to analyse the data with SPSS software.

Findings

The findings indicate that training and education, DL environment and communication support, continuation of usage intention, net benefits and user satisfaction are the critical success factors that play key role in ensuring the continued usage DL successful implementation in military context. The military-context DL needs to obtain critical success factors of DL practices implementation to sustain its continued usage, particularly for the active users of its members.

Research limitations/implications

This study only considered the military personnel who have visited the five main military libraries. For practical implications, the development of instruments in this study may be valuable tools to evaluate DL in other DL settings in Malaysian context other than academic settings.

Originality/value

This study makes a new contribution to DL IS successful implementation practices in military context. This study also provides important information for decision-makers involved in DL IS successful implementation practices and provides useful reference for future researchers in this research area.
Mixed methods research in tourism and hospitality journals
Authors: Truong Dao , Xiaoming Liu Rose , Yu Jing (Jasper)
Published: January 2020

Purpose

This paper aims to examine mixed methods research (MMR) that appeared in eight tourism and hospitality journals (“Annals of Tourism Research”, “Tourism Management”, “Journal of Travel Research”, “Journal of Sustainable Tourism”, “International Journal of Contemporary Hospitality Management”, “International Journal of Hospitality Management”, “Journal of Hospitality Marketing and Management” and “Journal of Hospitality and Tourism Research”) from 1998 to 2019.

Design/methodology/approach

This review paper was a mixed methods design and was conducted in three phases. In the first phase, a content analysis was performed to determine if each article could be classified as non-empirical, qualitative, quantitative or mixed methods. In the second phase, descriptive statistics was used to present the number and characteristics of MMR articles. In the third phase, the contributions of MMR to addressing particular issues in tourism and hospitality studies were investigated.

Findings

This study identified 753 mixed methods articles, wherein 482 articles (64%) were published in the chosen tourism publication outlets and 271 (36%) in the chosen hospitality publication outlets. MMR studies having a dominant focus on specific methods (459 articles; 61%) outnumbered those having an equal focus on the qualitative and quantitative parts (294 articles; 39%). In case one method was dominant, this was typically the quantitative. Sequential data collection was prevalent in most of the cases (94.2%). The contributions of MMR to addressing generic and specific research problems were also analyzed.

Originality/value

This is the first comparison of MMR in major tourism and hospitality journals.
LEGO®Serious Play®in multi-method tourism research
Authors: Wengel Yana
Published: January 2020

Purpose

In the past decade, scholars across social sciences shifted their attention towards creative and dynamic research methods. Despite the growing popularity of LEGO®Serious Play®method across social sciences, few studies applied the method in tourism and hospitality research. This method represents a powerful tool which uses a toy to solve problems, explore ideas and achieve objectives in business, research and community work. This paper aims to provide insights into qualitative multi-method approach incorporating LEGO®Serious Play®to gain a deeper understanding of hosts-guest experiences in volunteer tourism exchange programme.

Design/methodology/approach

The empirical material mentioned in the paper is based on an interpretive study investigating hosts-guest experiences on organic farms. The study used a multi-method approach, and the data were collected through unstructured interviews, observation, reflexive notes and LEGO®Serious Play®workshops with 32 participants in total.

Findings

The paper highlights the benefits and limitations of the qualitative multi-method study, specifically focusing on LEGO®Serious Play®as a novel approach for tourism and hospitality research.

Originality/value

This study contributes to making the current body of knowledge on qualitative multi-method methodologies and creative visual methodologies in the field of tourism and hospitality. As such, the paper provides an overview of the LEGO®Serious Play®method. Specifically, this exploratory paper brings attention to how and to what end existing LEGO®Serious Play®has been modified and adopted in this multi-method study. Furthermore, the paper highlights the future use to benefit the tourism and hospitality academics and industry professionals.
An evolutionary analysis of revenue management research in hospitality and tourism
Authors: Denizci Guillet Basak
Published: January 2020

Purpose

The purpose of this study is to examine the evolution of revenue management (RM) research’s intellectual structure in hospitality and tourism in an effort to initiate a creative discourse for RM scholars.

Design/methodology/approach

Co-citation analysis was used to examine the reference list of 343 articles over a 35-year period (1983-2018). Co-citation analysis focused on subject clustering and source knowledge evolution. Five periods were created to investigate the evolution of the RM field in the hospitality and tourism industry. The paradigm shift approach was adopted to acquire a better understanding of scientific evolution.

Findings

Findings indicated that from a Kuhnian perspective, RM research in hospitality and tourism did not go beyond the normal science phase. There is no current indication of anomalies in the form of conflict or questioning of the existing paradigms in RM research in hospitality and tourism. This might change, as the research in this realm develops further and evolves.

Research limitations/implications

This study identified issues related to research themes that have the potential of moving RM research in hospitality and tourism to the next level, enabling the paradigm shift in this discipline.

Originality/value

This study is instrumental in its outlook on the evolution of RM research’s intellectual structure in hospitality and tourism. In addition, it is the first study that considers the concept of paradigm shift in RM research context in hospitality and tourism.