bluuebunny/crossref_metadata_2025_split huggingface dataset:
N-acetyltransferase 2 genotypes amongst Zulu Speaking South Africans and isoniazid /N-acetyl-isoniazid pharmacokinetics during anti-tuberculosis treatment
Authors: Mthiyane Thuli , Millard James , Adamson John , Balakrishna Yusentha , Connolly Cathy , Owen Andrew , Rustomjee Roxana , Dheda Keertan , McIlleron Helen , Pym Alexander S. 
Published: December 2019

AbstractBackgroundDistribution ofN-acetyltransferase2(NAT2) polymorphisms varies considerably among different ethnic groups. Information onNAT2single-nucleotide polymorphisms in South African population is limited. We investigatedNAT2polymorphisms and their effect on isoniazid pharmacokinetics in Zulu black HIV-infected South Africans in Durban, South Africa. Methods: HIV-infected participants with culture-confirmed pulmonary tuberculosis (TB) were enrolled from two unrelated studies. Culture-confirmed participants were genotyped forNAT2polymorphisms 282C>T, 341T>C, 481C>T, 857G>A, 590G>A and 803A>G using Life Technologies pre-validated Taqman assays (Life Technologies, Paisley, UK). Participants underwent sampling for determination of plasma isoniazid andN-acetylisoniazid concentrations.ResultsAmongst the 120 patients, 63/120 (52.5%) were slow metabolisers (NAT2*5/*5), 43/120 (35.8%) had intermediate (NAT2*5/12), and 12/120 (11.7%) had rapid genotype (NAT2*4/*11, NAT2*11/12andNAT2*12/12). NAT2 alleles in this study were *4, *5C, *5D, *5E, *5J, *5K, *5KA, *5T, *11A, *12A/12C and *12M. NAT2*5 was the most frequent allele (70.4%) followed byNAT2*12 (27.9%). 34/40 had both PK results andNAT2genotyping results. The median area under the concentration-time-curve to infinity (AUC0-∞) interquartile range (IQR) was 7.81 (5.87 – 16.83) μg/ml/hr and maximum concentration (Cmax) 3.14 μg/ml (2.42 – 4.36) μg/mL. Individual polymorphisms were not equally distributed, with some represented in small numbers. Genotype did not correlate with phenotype, rapid genotype showing higher AUC0-∞than slow but not significant, p=0.43.ConclusionThere was high prevalence of slow followed by intermediate then rapid acetylator genotypes. The poor concordance between genotype and phenotype suggests that other factors or genetic loci influence INH metabolism, and warrants further investigation in this population.
Bacterial Genome wide association studies (bGWAS) and transcriptomics identifies cryptic antimicrobial resistance mechanisms in Acinetobacter baumannii
Authors: Roe Chandler , Williamson Charles H.D. , Vazquez Adam J. , Kyger Kristen , Valentine Michael , Bowers Jolene R. , Phillips Paul D. , Harrison Veronica , Driebe Elizabeth , Engelthaler David M. , Sahl Jason W. 
Published: December 2019

AbstractAntimicrobial resistance (AMR) in the nosocomial pathogen, Acinetobacter baumannii, is becoming a serious public health threat. While some mechanisms of AMR have been reported, understanding novel mechanisms of resistance is critical for identifying emerging resistance. One of the first steps in identifying novel AMR mechanisms is performing genotype/phenotype association studies. However, performing genotype/phenotype association studies is complicated by the plastic nature of the A. baumannii pan-genome. In this study, we compared the antibiograms of 12 antimicrobials associated with multiple drug families for 84 A. baumannii isolates, many isolated in Arizona, USA. in silico screening of these genomes for known AMR mechanisms failed to identify clear correlations for most drugs. We then performed a genome wide association study (GWAS) looking for associations between all possible 21-mers; this approach generally failed to identify mechanisms that explained the resistance phenotype. In order to decrease the genomic noise associated with population stratification, we compared four phylogenetically-related pairs of isolates with differing susceptibility profiles. RNA-Sequencing (RNA-Seq) was performed on paired isolates and differentially expressed genes were identified. In these isolate pairs, we identified four different potential mechanisms, highlighting the difficulty of broad AMR surveillance in this species. To verify and validate differential expression, amplicon sequencing was performed. These results suggest that a diagnostic platform based on gene expression rather than genomics alone may be beneficial in certain surveillance efforts. The implementation of such advanced diagnostics coupled with increased AMR surveillance will potentially improve A. baumannii infection treatment and patient outcomes.
Accurate Prediction of Kinase-Substrate Networks Using Knowledge Graphs
Authors: Nováček Vít , McGauran Gavin , Matallanas David , Blanco Adrián Vallejo , Conca Piero , Muñoz Emir , Costabello Luca , Kanakaraj Kamalesh , Nawaz Zeeshan , Mohamed Sameh K. , Vandenbussche Pierre-Yves , Ryan Colm , Kolch Walter , Fey Dirk 
Published: December 2019

AbstractPhosphorylation of specific substrates by protein kinases is a key control mechanism for vital cell-fate decisions and other cellular processes. However, discovering specific kinase-substrate relationships is timeconsuming and often rather serendipitous. Computational predictions alleviate these challenges, but the current approaches suffer from limitations like restricted kinome coverage and inaccuracy. They also typically utilise only local features without reflecting broader interaction context. To address these limitations, we have developed an alternative predictive model. It uses statistical relational learning on top of phosphorylation networks interpreted as knowledge graphs, a simple yet robust model for representing networked knowledge. Compared to a representative selection of six existing systems, our model has the highest kinome coverage and produces biologically valid high-confidence predictions not possible with the other tools. Specifically, we have experimentally validated predictions of previously unknown phosphorylations by the LATS1, AKT1, PKA and MST2 kinases in human. Thus, our tool is useful for focusing phosphoproteomic experiments, and facilitates the discovery of new phosphorylation reactions. Our model can be accessed publicly via an easy-to-use web interface (LinkPhinder).Author SummaryLinkPhinder is a new approach to prediction of protein signalling networks based on kinase-substrate relationships that outperforms existing approaches. Phosphorylation networks govern virtually all fundamental biochemical processes in cells, and thus have moved into the centre of interest in biology, medicine and drug development. Fundamentally different from current approaches, LinkPhinder is inherently network-based and makes use of the most recent AI de-velopments. We represent existing phosphorylation data as knowledge graphs, a format for large-scale and robust knowledge representation. Training a link prediction model on such a structure leads to novel, biologically valid phosphorylation network predictions that cannot be made with competing tools. Thus our new conceptual approach can lead to establishing a new niche of AI applications in computational biology.
Systems biology informed deep learning for inferring parameters and hidden dynamics
Authors: Yazdani Alireza , Lu Lu , Raissi Maziar , Karniadakis George Em 
Published: December 2019

AbstractMathematical models of biological reactions at the system-level lead to a set of ordinary differential equations with many unknown parameters that need to be inferred using relatively few experimental measurements. Having a reliable and robust algorithm for parameter inference and prediction of the hidden dynamics has been one of the core subjects in systems biology, and is the focus of this study. We have developed a new systems-biology-informed deep learning algorithm that incorporates the system of ordinary differential equations into the neural networks. Enforcing these equations effectively adds constraints to the optimization procedure that manifests itself as an imposed structure on the observational data. Using few scattered and noisy measurements, we are able to infer the dynamics of unobserved species, external forcing, and the unknown model parameters. We have successfully tested the algorithm for three different benchmark problems.Author summaryThe dynamics of systems biological processes are usually modeled using ordinary differential equations (ODEs), which introduce various unknown parameters that need to be estimated efficiently from noisy measurements of concentration for a few species only. In this work, we present a new “systems-informed neural network” to infer the dynamics of experimentally unobserved species as well as the unknown parameters in the system of equations. By incorporating the system of ODEs into the neural networks, we effectively add constraints to the optimization algorithm, which makes the method robust to noisy and sparse measurements.
Role of nitric oxide in improving seed germination and alleviation of copper-induced photosynthetic inhibition in Indian mustard
Authors: Rather Bilal A. , Mir Iqbal R. , Masood Asim , Anjum Naser A. , Khan Nafees A. 
Published: December 2019

AbstractHeavy metal stress limits crop production through its effects on seed germination and photosynthesis. Nitric oxide (NO), a versatile signaling molecule, plays a significant role in heavy metal stress tolerance. In the present investigation, the efficacy of NO application in the alleviation of copper (Cu) induced adverse impact on seed germination and photosynthesis of mustard plant (Brassica juncea L.) was evaluated. Pretreatment with NO donor sodium nitroprusside (SNP), significantly improved seed germination and alleviated Cu-accrued oxidative stress inB. junceaseeds. However, in the absence of NO, Cu showed a higher reduction in seed germination rate. Further, NO modulated the activities of antioxidant enzymes and sustained the lower level of lipid peroxidation by reducing H2O2,and thiobarbituric acid reactive substances (TBARS), thereby elevated the antioxidative capacity in Cu-exposed seeds. Seeds pretreated with NO also retained higher amylase activities for the proper seed germination when compared with control. NO mitigated Cu toxicity through an improved antioxidant system, and reducing Cu-induced accumulation of reactive oxygen species (ROS), reduction in lipid peroxidation improving photosynthetic efficiency and growth of the mustard plant. It may concluded that NO improved amylase activity, modulated activity of antioxidant enzymes, and enhanced the germination rate seeds under Cu stress, thereby improved photosynthesis and growth.
Understanding the genetic risks of complex diseases using the additive epistatic interaction model: a simulation study
Authors: Wang Yupeng 
Published: December 2019

AbstractThousands of Genome-Wide Association Studies (GWAS) have been carried out to pinpoint genetic variants associated with complex diseases. However, the proportion of phenotypic variance which can be explained by the identified genetic variants is relatively low, leading to the “missing heritability” problem. This problem may be partly caused by the inadequate understanding of the genetic mechanisms of complex diseases. Here, we propose the additive epistatic interaction model, consisting of widespread pure epistatic interactions whose effects are additive and can be summarized by a genetic risk score. Based on a simulated genotype dataset, the additive epistatic interaction model well depicted genetic risks and hereditary patterns of complex diseases. Based on the 1000 Genomes Project data, the additive epistatic interaction model accurately classified human populations. Moreover, the model’s genetic risk score can be replaced by a deep learning model which is more resistant to noises. We suggest that the additive epistatic interaction model may help to understand the genetic mechanisms and risks of complex diseases.
Modulation of the combinatorial code of odorant receptor response patterns in odorant mixtures
Authors: de March Claire A. , Titlow William B. , Sengoku Tomoko , Breheny Patrick , Matsunami Hiroaki , McClintock Timothy S. 
Published: December 2019

AbstractThe perception of odors relies on combinatorial codes consisting of odorant receptor (OR) response patterns to encode odor identity. The modulation of these patterns by odorant interactions at ORs potentially explains several olfactory phenomena: mixture suppression, unpredictable sensory outcomes, and the perception of odorant mixtures as unique objects. We determined OR response patterns to 4 odorants and 3 binary mixtures in vivo in mice, identifying 30 responsive ORs. These patterns typically had a few strongly responsive ORs and a greater number of weakly responsive ORs. The ORs responsive to an odorant were often unrelated sequences distributed across several OR subfamilies. Mixture responses predicted pharmacological interactions between odorants, which were tested in vitro by heterologous expression of ORs in cultured cells. These tests provided independent evidence confirming odorant agonists for 13 ORs and identified both suppressive and additive effects of mixing odorants. This included 11 instances of antagonism of ORs by an odorant, 1 instance of additive responses to a binary mixture, 1 instance of suppression of a strong agonist by a weak agonist, and the discovery of an inverse agonist for an OR. These findings demonstrate that interactions between odorants at ORs are common.
Optogenetic control of PRC1 reveals that bridging fibers promote chromosome alignment by overlap length-dependent forces
Authors: Jagrić Mihaela , Risteski Patrik , Martinčić Jelena , Milas Ana , Tolić Iva M. 
Published: December 2019

AbstractDuring metaphase, chromosome position at the spindle equator is regulated by the forces exerted by kinetochore microtubules and polar ejection forces. However, the role of forces arising from mechanical coupling of sister kinetochore fibers with bridging fibers in chromosome alignment is unknown. Here we develop an optogenetic approach for acute removal of PRC1 to disassemble bridging fibers, and show that they promote chromosome alignment. Tracking of the plus-end protein EB3 revealed longer antiparallel overlaps of bridging microtubules upon PRC1 removal, which was accompanied by misaligned and lagging kinetochores. Kif4A/kinesin-4 and Kif18A/kinesin-8 were found within the bridging fiber and lost upon PRC1 removal, suggesting that these proteins regulate the overlap length of bridging microtubules. We propose that PRC1-mediated crosslinking of bridging microtubules and recruitment of kinesins to the bridging fiber promotes chromosome alignment by overlap length-dependent forces transmitted to the associated kinetochores fibers.
Nanometric axial localization of single fluorescent molecules with modulated excitation
Authors: Jouchet Pierre , Cabriel Clément , Bourg Nicolas , Bardou Marion , Poüs Christian , Fort Emmanuel , Lévêque-Fort Sandrine 
Published: December 2019

AbstractStrategies have been developed in LIDAR to perform distance measurements for non-coherent emission in sparse samples based on excitation modulation. Super-resolution fluorescence microscopy is also striving to perform axial localization but through entirely different approaches. Here we revisit the amplitude modulated LIDAR approach to reach nanometric localization precision and we successfully adapt it to bring distinct advantages to super-resolution microscopy. The excitation pattern is performed by interference enabling the decoupling between spatial and time modulation. The localization of a single emitter is performed by measuring the relative phase of its linear fluorescent response to the known shifting excitation field. Taking advantage of a tilted interfering configuration, we obtain a typical axial localization precision of 7.5 nm over the entire field of view and the axial capture range, without compromising on the acquisition time, the emitter density or the lateral localization precision. The interfering pattern being robust to optical aberrations, this modulated localization (ModLoc) strategy is particularly well suited for observations deep in the samples. Images performed on various biological samples show that the localization precision remains nearly constant up to several micrometers.
A framework of online-merge-offline (OMO) classroom for open education
Authors: Xiao Jun , Sun-Lin Hong-Zheng , Cheng Hsu-Chen 
Published: December 2019

Purpose
The purpose of this paper is to propose a design of online-merge-offline (OMO) classroom for open education with design principles related to practical issues of teachers’ teaching, students’ learning and schools’ management.

Design/methodology/approach
Three stages were covered: drafted an OMO classroom framework, built a sample classroom and explored end-users’ experience. First, authors searched for and reviewed previous studies and related cases to draft an OMO framework. Second, a classroom, consisted of wireless devices, cloud-based services, Internet of Things terminals, ergonomics furniture, and comprehensive data management and analysis services, was built in Shanghai Open University. Third, invited 11 students’, 18 teachers’ and 9 school managers’ perspectives were collected and analysed by surveys and interviews.

Findings
All student participants responded positively in terms of learning experience in the classroom. They not only engaged in classroom activities such, but also accessed needed learning materials and interacted with teachers and peers anytime anywhere via mobile devices. Similarly, most teachers (90 per cent) made positive responses because of flexibility of teaching strategies and learning activities and expressed willingness to use the classroom in the future (94.4 per cent). In addition, more than 78 per cent of managers positively commented on the design of classroom, interaction effects and effective management. Visualised data allowed them to timely monitor status of facilities, comprehensively understand users’ behaviour and issues, make necessary decision with scientific evidence.

Research limitations/implications
The framework and classroom not only provide teachers, students, school managers and researcher with a better understanding of innovative open education, but also indicate the key role of objective-oriented and data-driven issues for further work.

Originality/value
To meet needs of teachers, students, managers and researchers in today’s open education, an OMO classroom was built in Shanghai Open University based on the proposed Objective-Oriented Pedagogy-Space-Technology (OPST) framework. The framework provides readers (especially teachers and administrators of open-education institutes, staff of information centres and ed-tech researchers) with a better understanding of innovative instruction and effective management, and the originally designed classroom can be a practical and illuminating example.
L&D professionals in organisations: much ambition, unfilled promise
Authors: Garavan Thomas N. , Heneghan Sinead , O’Brien Fergal , Gubbins Claire , Lai Yanqing , Carbery Ronan , Duggan James , Lannon Ronnie , Sheehan Maura , Grant Kirsteen 
Published: December 2019

PurposeThis monograph reports on the strategic and operational roles of learning and development (L&D) professionals in Irish, UK European and US organisations including multinational corporations, small to medium enterprises, the public sector and not for profit organisations. This paper aims to investigate the contextual factors influencing L&D roles in organisations, the strategic and operational roles that L&D professionals play in organisations, the competencies and career trajectories of L&D professionals, the perceptions of multiple internal stakeholders of the effectiveness of L&D roles and the relationships between context, L&D roles, competencies/expertise and perceived organisational effectiveness.Design/methodology/approachThe study findings are based on the use of multiple methods. The authors gathered data from executives, senior managers, line managers, employee and L&D professionals using multiple methods: a survey (n= 440), Delphi study (n= 125) and semi-structured interviews (n= 30).FindingsThe analysis revealed that L&D professionals increasingly respond to a multiplicity of external and internal contextual influences and internal stakeholders perceived the effectiveness of L&D professionals differently with significant gaps in perceptions of what L&D contributes to organisational effectiveness. L&D professionals perform both strategic and operational roles in organisations and they progress through four career levels. Each L&D role and career level requires a distinct and unique set of foundational competencies and L&D expertise. The authors found that different contextual predictors were important in explaining the perceived effectiveness of L&D roles and the importance attached to different foundational competencies and areas of L&D expertise.Originality/valueThis is one of the few studies to have investigated the L&D professional role in organisations from the perspective of multiple stakeholders using multiple research methods.
Investigating the view of quality management success factors amongst future early career operations leaders
Authors: Shokri Alireza 
Published: December 2019

Purpose
The study aims to investigate the gap between the current vision and knowledge of future early career operations leaders (OL) and common strategic total quality management (TQM) frameworks such as Malcolm Baldrige National Quality Awards and competing value framework.

Design/methodology/approach
A survey questionnaire was developed for different groups of participants as current higher education students to identify the gap and analyse the significance of these groups on the factors in TQM framework. The Kruskal–Wallis test as the non-parametric quantitative analysis technique was adopted for this study.

Findings
A new set of TQM factors with necessity of more knowledge and understanding of future generation was identified, followed by highlighting clear differences amongst different groups of this generation in terms of their demographic measures, perceived leadership style and organisational culture.

Research limitations/implications
This research study contributed significantly to the existing study about common QM models and their integration with theories relevant to organisational culture and leadership. The data collection can be extended further in the higher education sector or beyond that.

Practical implications
A sustainable operations leadership practice needs managers and leaders with a sustainable knowledge development of quality management; and as a result of this study, the current vision of future young OL would not echo this.

Originality/value
This study has a systematic, non-parametric approach towards currently fragmented QM analysis, and is integrated with human resource and visionary elements of future young OL and universal QM models and theories.