bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genome-Wide Association for Itraconazole Sensitivity in Non-Resistant Clinical Isolates ofAspergillus fumigatus
Authors: Zhao Shu , Ge Wenbo , Watanabe Akira , Fortwendel Jarrod R. , Gibbons John G. 
Published: September 2020

AbstractAspergillus fumigatusis a potentially lethal opportunistic pathogen that infects over ∼200,000 people and causes ∼100,000 deaths per year globally. TreatingA. fumigatusinfections is particularly challenging because of the recent emergence of azole-resistance. The majority of studies focusing on the molecular mechanisms underlying azole resistance have examined azole-resistant isolates. However, isolates that are susceptible to azoles also display variation in their sensitivity, presenting a unique opportunity to identify genes contributing to azole sensitivity. Here, we used genome-wide association (GWA) analysis to identify loci involved in azole sensitivity by analyzing the association between 68,853 SNPs and itraconazole (ITCZ) minimum inhibitory concentration (MIC) in 76 clinical isolates ofA. fumigatusfrom Japan. Population structure analysis suggests the presence of four distinct populations, with ITCZ MICs distributed relatively evenly across populations. We independently conducted GWA when treating ITCZ MIC as a quantitative trait and a binary trait and identified two SNPs with strong associations that were identified in both analyses. These SNPs fell within the coding regions ofAfu2g02220andAfu2g02140. We functionally validatedAfu2g02220by knocking it out using a CRISPR/Cas-9 approach, because orthologs of this gene are involved in sterol modification and ITCZ targets the ergosterol pathway. Knockout strains displayed no difference in growth compared to the parent strain in minimal media, yet a minor but consistent inhibition of growth in the presence of 0.15 ug/ml ITCZ. Our results suggest that GWA paired with efficient gene deletion is a powerful and unbiased strategy for identifying the genetic basis of complex traits inA. fumigatus.ImportanceAspergillus fumigatusis a pathogenic mold that can infect and kill individuals with compromised immune systems. The azole class of drugs provide antifungal activity againstA. fumigatusinfections and have become an essential treatment strategy. Unfortunately,A. fumigatusazole resistance has recently emerged and rapidly risen in frequency making treatment more challenging. Our understanding of the molecular basis of azole sensitivity has been shaped mainly through candidate gene studies. Unbiased approaches are necessary to understand the full repertoire of genes and genetic variants underlying azole resistance and sensitivity. Here, we provide the first application of genome-wide association analysis inA. fumigatusin the identification of a gene (Afu2g02220) that contributes to itraconazole susceptibility. Our approach, which combines association mapping and CRISPR/Cas-9 for functional validation of candidate genes, has broad application for investigating the genetic basis of complex traits in fungal systems.
In vivotranscriptome analysis provides insights into host-dependent expression of virulence factors byYersinia entomophagaMH96, during infection ofGalleria mellonella
Authors: Paulson Amber R. , O’Callaghan Maureen , Zhang Xue-Xian , Rainey Paul B. , Hurst Mark R.H. 
Published: September 2020

AbstractThe function of microbes can be inferred from knowledge of genes specifically expressed in natural environments. Here we report thein vivotranscriptome of the entomopathogenic bacteriumYersinia entomophagaMH96, captured during three stages of intrahemocoelic infection inGalleria mellonella. A total of 1,285 genes were significantly upregulated by MH96 during infection; 829 genes responded toin vivoconditions during at least one stage of infection, 289 responded during two stages of infection and 167 transcripts responded throughout all three stages of infection. Genes upregulated during the earliest infection stage included components of the insecticidal toxin complex Yen-TC (chi1, chi2andyenC1), genes for rearrangement hotspot element containing proteinyenC3, cytolethal distending toxincdtABand vegetative insecticidal toxinvip2. Genes more highly expressed throughout the infection cycle included the putative heat-stable enterotoxinyenTand three adhesins (usher-chaperone fimbria, filamentous hemagglutinin and an AidA-like secreted adhesin). Clustering and functional enrichment of gene expression data also revealed expression of genes encoding type III and VI secretion system-associated effectors. Together these data provide insight into the pathobiology of MH96 and serve as an important resource supporting efforts to identify novel insecticidal agents.
Severe childhood and adulthood stress associates with neocortical layer-specific reductions of mature spines in psychiatric disorders
Authors: Kaul Dominic , Smith Caine C , Stevens Julia , Fröhlich Anna S , Binder Elisabeth B , Mechawar Naguib , Schwab Sibylle G , Matosin Natalie 
Published: September 2020

AbstractSevere stress exposure causes the loss of dendritic spines on cortical pyramidal neurons and induces psychiatric-like symptoms in rodent models. These effects are strongest following early-life stress and are most persistent on apical dendrites. However, the long-term impacts and temporal effects of stress exposure on the human brain remain poorly understood. Using a novel postmortem cohort of psychiatric cases with severe stress experienced in childhood, adulthood, or no severe stress, and matched controls, we aimed to determine the impact of stress timing on pyramidal neuron structure in the human orbitofrontal cortex (OFC). We performed Golgi Cox staining and manually measured the morphology and density of over 22,000 dendritic spines on layer-specific pyramidal neuron apical dendrites. We also quantified glucocorticoid receptor mRNA and protein as a marker of stress dysregulation. Both childhood and adulthood stress were associated with large reductions in mature mushroom spine density (up to 56% loss) in both the superficial (II/III) and deeper layers (V) of the OFC. However, childhood stress caused more substantial reductions to both total and mature mushroom spines. No difference in glucocorticoid receptor mRNA and protein were seen between groups, although both negatively correlated with total spine density within the whole cohort. These findings indicate that severe stress, especially when experienced during childhood, persistently affects the fine morphological properties of neurons in the human OFC. This may impact on cell connectivity in this brain area, and at least partly explain the social and emotional symptoms that originate in the OFC in psychiatric disorders.
NAD(H)-mediated tetramerization controls the activity ofLegionella pneumophilaphospholipase PlaB
Authors: Diwo Maurice , Michel Wiebke , Aurass Philipp , Kuhle-Keindorf Katja , Pippel Jan , Krausze Joern , Lang Christina , Blankenfeldt Wulf , Flieger Antje 
Published: September 2020

AbstractThe virulence factor and phospholipase PlaB promotes lung colonization, tissue destruction, and intracellular replication ofLegionella pneumophila, the causative agent of Legionnaires’ disease. It is exposed at the bacterial surface and shows an extraordinary activation mechanism by tetramer deoligomerization. To unravel the molecular basis for enzyme activation and localization, we determined the crystal structure of PlaB in its tetrameric form. We found that the tetramer is a dimer of identical dimers, and a monomer consists of an N-terminal phospholipase α/β-hydrolase domain augmented by two non-canonical two-stranded β-sheets, β6/β7 and β9/β10. The C- terminal domain reveals a novel fold displaying a bilobed β-sandwich with a hook structure that is required for dimer formation and complementation of the phospholipase domain in the neighboring monomer. Unexpectedly, we observed eight NAD(H) molecules at the dimer/dimer interface, suggesting that these molecules stabilize the tetramer and hence lead to enzyme inactivation. Indeed, addition of NAD(H) increased the fraction of the tetrameric form and concomitantly reduced activity. β9/β10 mutants revealed a decrease in the tetrameric fraction, altered activity profiles, and mislocalization. Protein variants lacking the hook or strands β6/β7 were unaffected in terms of localization but lost their activity, and lid mutants changed substrate specificity. Together, these data reveal structural elements and an unprecedented NAD(H)- mediated tetramerization mechanism required for spatial and enzymatic control of a phospholipase virulence factor. The regulatory process identified is ideally suited to fine tune PlaB in a way that protectsL. pneumophilafrom self-inflicted lysis while ensuring its activity at the pathogen–host interface.
Polygenic mutations model the pleiotropic disease of Fanconi Anemia
Authors: Tomaszowski Karl-Heinz , Roy Sunetra , Keshvani Caezaan , Ott Martina , DiNardo Courtney , Schindler Detlev , Schlacher Katharina 
Published: September 2020

AbstractFanconi Anemia (FA) is a prototypic genetic disease signified by heterogeneous phenotypes including cancer, bone marrow failure, short stature, congenital abnormalities, infertility, sub-mendelian birth rate, genome instability and high cellular sensitivity to cancer therapeutics1-4. Clinical diagnosis is confirmed by identifying biallelic, homo- or hemizygous mutations in any one of twenty-threeFANCgenes1,5. Puzzlingly, inactivation of one singleFancgene in mice fails to faithfully model the human disease manifestations6-8. We here delineate a preclinicalFancmouse model with mutations in two genes,Fancd1/Brca2andFanco/Rad51c, that recapitulates the severity and heterogeneity of the human disease manifestations including death by cancer at young age. Surprisingly, these grave phenotypes cannot be explained by the sum of phenotypes seen in mice with single gene inactivation, which are unremarkable. In contrast to expectations from classic epistasis analysis of genetic pathways, the data instead reveal an unexpected functional synergism of polygenicFancmutations. Importantly in humans, whole exome sequencing uncovers thatFANCco-mutation in addition to the identified inactivatingFANCgene mutation is a frequent event in FA patients. Collectively, the data establish a concept of polygenic stress as an important contributor to disease manifestations, with implications for molecular diagnostics.
Lysozyme crystals dyed with bromophenol blue: where has the dye gone?
Authors: Plaza-Garrido Marina , Salinas-Garcia M. Carmen , Alba-Elena Daniel , Martínez Jose C. , Camara-Artigas Ana 
Published: September 2020

Protein crystals can easily be coloured by adding dyes to their mother liquor, but most structures of these protein–dye complexes remain unsolved. Here, structures of lysozyme in complex with bromophenol blue obtained by soaking orthorhombic and tetragonal crystals in a saturated solution of the dye at different pH values from 5.0 to 7.5 are reported. Two different binding sites can be found in the lysozyme–bromophenol blue crystals: binding site I is located near the amino- and carboxyl-termini, while binding site II is located adjacent to helices α1 (residues 4–15) and α3 (residues 88–100). In the orthorhombic crystals soaked at pH 7.0, binding of the dye takes place in both sites without significant changes in the unit cell. However, soaking tetragonal crystals with bromophenol blue results in two different complexes. Crystals soaked at pH 5.5 (HEWL-T1) show a single dye molecule bound to site II, and the crystals belong to space group P43212 without significant changes in the unit cell (a = b = 78.50, c = 37.34 Å). On the other hand, crystals soaked at pH 6.5 in the presence of imidazole (HEWL-T2) show up to eight molecules of the dye bound to site II, and display changes in space group (P212121) and unit cell (a = 38.00, b = 76.65, c = 84.86 Å). In all of the structures, the dye molecules are placed at the surface of the protein near to positively charged residues accessible through the main solvent channels of the crystal. Differences in the arrangement of the dye molecules at the surface of the protein suggest that the binding is not specific and is mainly driven by electrostatic interactions.
How can econometrics help fight the COVID-19 pandemic?
Authors: Alvarez Kevin , Kreinovich Vladik 
Published: September 2020

Purpose
The current pandemic is difficult to model – and thus difficult to control. In contrast to the previous epidemics, whose dynamics were smooth and well described by the existing models, the statistics of the current pandemic are highly oscillating. The purpose of this paper is to explain these oscillations and to see how this explanation can be used to fight the epidemic.

Design/methodology/approach
The authors use an analogy with economic systems.

Findings
The authors show that these oscillations can be explained if we take into account the disease’s long incubation period – as a result of which our control measures are determined by outdated data, showing number of infected people two weeks ago. To better control the pandemic, the authors propose to use the experience of economics, where also the effect of different measures can be observed only after some time. In the past, this led to wild oscillations of the economy, with rapid growth periods followed by devastating crises. In time, economists learned how to smooth the cycles and thus to drastically decrease the corresponding negative effects. The authors hope that this experience can help fight the pandemic.

Originality/value
To the best of our knowledge, this is the first explanation of the highly oscillatory nature of this epidemic’s dynamics.
Gender and body weight status differences in the consumption frequency, choice and sugar intake of ready-to-drink sugar-sweetened beverages
Authors: Tan Seok Tyug , Abdullah Zaini Nur Ainaa' Najihah , Tan Seok Shin , Tan Chin Xuan 
Published: September 2020

PurposeFrequent consumption of sugar-sweetened beverages (SSB) not only contribute to the incidence of dental caries but also a substantial risk for metabolic syndrome, obesity, type 2 diabetes mellitus, cardiovascular diseases and arthritis. Therefore, this study aims to compare the ready-to-drink SSB (RTD-SSB) consumption frequency, choice and sugar intake across gender and body weight status.Design/methodology/approachThis cross-sectional study involved 126 adolescents from two primary schools in Shah Alam, Selangor. Adolescents aged between 9-11 years old were enrolled using convenience sampling method. A semi-structured questionnaire was administered to assess socio-demographic and RTD-SSB consumption of the adolescents. The RTD-SSB consumption was assessed with 2-day 24-hour dietary recalls (single weekend and single weekday recalls), whereas body weight and height were assessed using TANITA weighing scale and stadiometer, respectively. Data were analysed using SPSS version 26.0, while BMI-for-age (BAZ) z-score was determined using the World Health Organization (WHO) AnthroPlus software version 1.0.4.FindingsThe mean age of 126 adolescents was 10.82 ± 0.93 years old. The frequency of SSB consumption was 1.77 ± 1.25 times/day, whereas the average daily sugar intake was 6.3 teaspoons (26.61 ± 22.18 g) from RTD-SSBs. Flavoured milk emerged as the most frequent consumed beverage among adolescents, regardless of gender and weight status. No association was observed between the RTD-SSB consumption frequency and weight status (χ2 = 0.953, p > 0.05) as well as sugar intake and weight status (χ2 = 1.202, p > 0.05). Emerging findings demonstrated that the RTD-SSB consumption frequency, choice and sugar intake were similar across gender and weight status.Originality/valueThis was the first study that compares RTD-SSB consumption frequency, choice and sugar intake across gender and different body weight status.
Training transfer climate: examining the role of high performance work system and organizational performance in the power sector of India
Authors: Muduli Ashutosh , McLean Gary N. 
Published: September 2020

PurposeBenchmarking research has explored the role of organizational practices and business processes rooted with human capabilities for achieving growth performance. The role of high performance work system as an organizational practice and business process is yet to be studied. Even if studied, no study has been conducted on the role of training transfer climate on high performance work system and organizational performance. The current research aims at examining high performance work system on organizational performance. Further, the study also examine training transfer climate as a mediating variable between HPWS and organizational performance.Design/methodology/approachData collected from 415 executives of a high performance-based power sector company of Gujarat, India. The survey instrument consists of high performance work system, training transfer climate and organizational performance. Confirmatory factor analysis was used for a simultaneous assessment of overall and specific elements of measurement validity and reliability. Structural equation modelling used to test the hypothesized model.FindingsThe result proved the capability of high performance work system to predict organizational performance. Further, the result supports the hypothesis that training transfer climate acts as a mediator between high performance work system and organizational performance.Research limitations/implicationsThe result has important theoretical and managerial implications. Theoretically, the research extends the scope of benchmarking to high performance work system. The managerial implications have been discussed from the training transfer climate perspectives.Originality/valueThe originality of the study lies with proving the role of high performance work system and training transfer climate as an organizational practice and business process within benchmarking research.
Impact of firm performance and corporate governance mechanisms on intellectual capital disclosures in CEO statements
Authors: Mardini Ghassan H. , Lahyani Fathia Elleuch 
Published: September 2020

PurposeUsing agency theory and impression management theory, this study examines the impact of financial performance (FP) and corporate governance (CG) mechanisms on the extent of intellectual capital disclosures (ICDs) and the three components within the CEO statement – human capital (HC), structural capital (SC) and relational capital (RC).Design/methodology/approachThis study employs a sample of non-financial SPF-120 French listed firms to capture the relevant variables; it collects data for 2010–2017, using a panel data technique to run the random effects regressions.FindingsThe study finds that FP, measured using both market (Tobin's q) and accounting (return on equity and return on assets) indicators, plays a vital role in the extent of ICDs and the three components in the CEO statement published by SPF-120 companies. This confirms its impact on the decision-making needs of stakeholders. Among the CG mechanisms, this study finds that cultural diversity and gender diversity affect some ICD components. Moreover, CEO characteristics such as age, education and role duality affect ICD, while institutional ownership drives the extent of such disclosures.Practical implicationsOur findings have comprehensive implications for managers of French listed firms, the Autorité des Marchés Financiers, and stakeholders in general.Originality/valueThis study provides significant insights by investigating the impact of FP, CG and company characteristics on the extent of the ICDs published in CEO statements.
Exploring the determinants of scientific productivity: a proposed typology of researchers
Authors: Ballesteros-Rodríguez José Luis , De Saá-Pérez Petra , García-Carbonell Natalia , Martín-Alcázar Fernando , Sánchez-Gardey Gonzalo 
Published: September 2020

PurposeAlthough several previous studies were focused on examining the determinants of research productivity, the knowledge of the competences and motives that lead researchers to achieve relevant scientific performance remains unclear. This paper is aimed at contributing to this gap in the research by proposing a typology to understand academic researchers' traits and extending the traditional “more is better” approach, which assumes that higher levels of competence and motivation are always preferable.Design/methodology/approachCluster analysis was applied to a sample of 471 Spanish academics to examine diverse combinations of human capital attributes – knowledge, skills, and abilities – and two sources of motivation – intrinsic and extrinsic.FindingsFour researcher profiles were identified: (1) high vocational academics; (2) motivated academics; (3) self-starter academics and (4) reactive academics. Based on these preliminary findings, we present conclusions about the functioning and productivity of academic researchers.Originality/valueThis paper contributes a novel typology of researchers to the extant literature based on the variables of academic human capital and motivation. The findings indicate that a required and specific combination of attributes better fits the reality of research activities.
Lowering the walls: an integrative approach to first-year undergraduate business education
Authors: Fernando Mario , Fox Stephen , Bandara Ruwan , Hartley Daniel 
Published: September 2020

PurposeThe purpose of this study is to examine the nature of interdisciplinary thinking and the conditions and processes that foster it among first-year undergraduate students.Design/methodology/approachThis study with 510 Australian students drawn from 2 cohorts explored an initiative to promote interdisciplinary teaching in an undergraduate ethics-based subject. The study focused on a case-study-based reflective essay intervention to compare the teaching and learning outcomes in the two student cohorts.FindingsThe results show how a case-study-based reflective essay intervention impacted on interdisciplinary learning. Introducing the case-study-based reflective essay improved interdisciplinary thinking. Findings show that integral to engaging students in interdisciplinary learning is a need for more experiential and active approaches built into education itself.Research limitations/implicationsThe study findings extend Speltet al.’s (2009) model in the business education context to link student learning outcomes to the learning processes, learning environment and interdisciplinary thinking. A key limitation of this study is that the intervention is limited to only two student cohorts.Practical implicationsThe study recommends the use of reflective practice in interdisciplinary subjects to support a variety of learning outcomes across disciplines including classroom-based and assignment-based reflective practices which influence interdisciplinary thinking and active learning.Originality/valueThere is limited understanding on how business schools should or could attempt to promote interdisciplinary teaching and the actual methods for doing so. This study highlights the significance of integrating reflective practice in undergraduate business education to promote students’ interdisciplinary thinking.