bluuebunny/crossref_metadata_2025 huggingface dataset:
Addressing the Most Neglected Diseases through an Open Research Model: the Discovery of Fenarimols as Novel Drug Candidates for Eumycetoma
Authors: Lim Wilson , Melse Youri , Konings Mickey , Duong Hung Phat , Eadie Kimberly , Laleu Benoît , Perry Ben , Todd Matthew H. , Ioset Jean-Robert , van de Sande Wendy W.J.
Published: February 2018

Eumycetoma is a chronic infectious disease characterized by a large subcutaneous mass, often caused by the fungusMadurella mycetomatis.A combination of surgery and prolonged medication is needed to treat this infection with a success rate of only 30%. There is, therefore, an urgent need to find more effective drugs for the treatment of this disease. In this study, we screened 800 diverse drug-like molecules and identified 215 molecules that were activein vitro.Minimal inhibitory concentrations were determined for the 13 most active compounds. One of the most potent compounds, a fenarimol analogue for which a large analogue library is available, led to the screening of an additional 35 compounds for theirin vitroactivity againstM. mycetomatishyphae, rendering four further hit compounds. To assess thein vivopotency of these hit compounds, aGalleria mellonellalarvae model infected withM. mycetomatiswas used. Several of the compounds identifiedin vitrodemonstrated promising efficacyin vivoin terms of prolonged larval survival and/or reduced fungal burden. The results presented in this paper are the starting point of anOpen Source Mycetoma (MycetOS)approach in which members of the global scientific community are invited to participate and contribute as equal partners. We hope that this initiative, coupled with the promising new hits we have reported, will lead to progress in drug discovery for this most neglected of neglected tropical diseases.

Author summary

Mycetoma is a poverty-associated disease that was recently recognised as a neglected tropical disease by the World Health Organisation (WHO). This disease can be caused by either bacteria (actinomycetoma) or fungi (eumycetoma). The most common causative agent of mycetoma is the fungusMadurella mycetomatis.Actinomycetoma can be easily treated, but for eumycetoma, the current and only antifungal drug used is only able to successfully treat 30% of patients. Treatment often involves prolonged medication use and amputation of the affected area. This disease is disfiguring and is a social stigma for patients in endemic countries. To improve treatment for patients, we have looked at over 800 diverse drug-like molecules and compounds in hope to develop new drugs in this study. We have identified 215 compounds with activity againstM. mycetomatisin vitro and several in vivo with ourGalleria mellonellalarvae model. We have chosen an open source approach with this study and placed our findings in an online database and made it available to the public. We invite the global scientific community to participate in our study and contribute as equal partners as long as an open source approach is held in hopes to fast track and boost drug discovery for Eumycetoma.
Mathematical Modelling of Actin treadmill in Apicomplexans
Authors: Prajapat Mahendra , Pathak Samridhi , Gauba Ricka , Kale Avinash , Saini Supreet
Published: February 2018

Plasmodium parasite, a representative member of phylum Apicomplexa is a causative agent of malaria in human as well as other animals. To infect host cells, Plasmodium first finds receptors on the host cell surface, then binds specifically, and finally penetrates host cell membrane to acquire the host cellular resources. The motility for moving on the cell surface is equipped by the precise and tight control of actin treadmill. Several regulators are required to achieve precision and robustness in the control of actin treadmill. However, the mechanistic detail of the treadmill regulatory network and the cross-talk among regulators are not well understood. We developed a stochastic model of treadmill regulation and explored the dynamics of filament growth, nucleation time, and elongation time. Our study mainly highlighted on how and what helps cells to maintain an average size of the actin filaments within a species. This is particularly important, since, excessive growth of filament can lead to cell lysis. Moreover, we also explore how the regulators interact to fine-tune the control elements in the actin treadmill.
Determination of growth-coupling strategies and their underlying principles
Authors: Alter Tobias B. , Blank Lars M. , Ebert Birgitta E.
Published: February 2018

Metabolic coupling of product synthesis and microbial growth is a prominent approach for maximizing production performance. Growth-coupling (GC) also helps stabilizing target production and allows the selection of superior production strains by adaptive laboratory evolution. We have developed the computational tool gcOpt, which identifies knockout strategies leading to the best possible GC by maximizing the minimally guaranteed product yield. gcOpt implicitly favors solutions resulting in strict coupling of product synthesis to growth and metabolic activity while avoiding solutions inferring weak, conditional coupling.

GC intervention strategies identified by gcOpt were examined for GC generating principles under diverse conditions. Curtailing the metabolism to render product formation an essential carbon drain was identified as one major strategy generating strong coupling of metabolic activity and target synthesis. Impeding the balancing of cofactors and protons in the absence of target production was the underlying principle of all other strategies and further increased the GC strength of the aforementioned strategies. Thus, generating a dependency between supply of global metabolic cofactors and product synthesis appears to be advantageous in enforcing strong GC.

Abbreviations

ATP

Adenosine triphosphate

ATPM

ATP maintenance requirements reaction

ATPcsc

Carbon specific ATP synthesis capability

ATPsc

ATP synthesis capability

CoA

Coenzyme A

EM

Elementary mode

EMA

Elementary modes analysis

FBA

Flux balance analysis

GC

Growth-coupling

GCS

Growth-coupling strength

H+

Proton

hGC

Holistic growth-coupling

MCS

Minimal cut sets

MILP

Mixed integer linear program

NAD+

Nicotinamide adenine dinucleotide (oxidized)

NADH

Nicotinamide adenine dinucleotide (reduced)

NADP+

Nicotinamide adenine dinucleotide phosphate (oxidized)

NADPH

Nicotinamide adenine dinucleotide phosphate (reduced)

NGAM

Non-growth associated maintenance

Pi

Phosphate molecule

PPP

Pentose phosphate pathway

sGC

Strong growth-coupling

wGC

Weak growth-coupling
MVP: predicting pathogenicity of missense variants by deep learning
Authors: Qi Hongjian , Chen Chen , Zhang Haicang , Long John J. , Chung Wendy K. , Guan Yongtao , Shen Yufeng
Published: February 2018

Accurate pathogenicity prediction of missense variants is critical to improve power in genetic studies and accurate interpretation in clinical genetic testing. Here we describe a new prediction method, MVP, which uses a deep learning approach to leverage large training data sets and many correlated predictors. Using cancer mutation hotspots and de novo germline mutations from developmental disorders for benchmarking, MVP achieved better performance in prioritizing pathogenic missense variants than previous methods.
Standardized Informatics Computing Platform for Advancing Biomedical Discovery Through Data Sharing
Authors: Navale Vivek , Ji Michelle , McCreedy Evan , Gebremichael Tsega , Garcia Alison , Misquitta Leonie , Lin Ching-Heng , Fann Yang , McAuliffe Matthew
Published: February 2018

Objective

The goal is to develop a standardized informatics computing system that can support end-to-end research data lifecycle management for biomedical research applications.

Materials and Methods

Design and implementation of biomedical research informatics computing system (BRICS) is demonstrated. The system architecture is modular in design with several integrated tools: global unique identifier, validation, upload, download and query tools that support user friendly informatics system capability.

Results

BRICS instances were deployed to support research for improvements in diagnosis of traumatic brain injury, biomarker discovery for Parkinson’s Disease, the National Ophthalmic Disease Genotyping and Phenotyping network, the informatics core for the Center for Neuroscience and Regenerative Medicine, the Common Data Repository for Nursing Science, Global Rare Diseases Patient Registry, and National Institute of Neurological Disorders and Stroke Clinical Informatics system for trials and research.

Discussion

Data deidentification is conducted by using global unique identifier methodology. No personally identifiable information exists on the BRICS supported repositories. The Data Dictionary provides defined Common Data Elements and Unique Data Elements, specific to each of the BRICS instance that enables Query Tool to search through research data. All instances are supported by the Medical Imaging Processing, statistical analysis R, and Visualization software program.

Conclusion

The BRICS core modules can be easily adapted for various biomedical research needs thereby reducing cost in developing new instances for additional biomedical research needs. It provides user friendly tools for researchers to query and aggregate genetic, phenotypic, clinical and medical imaging data. Data sets are findable, accessible and reusable for researchers to foster new research on various diseases.
Convergent evolution of gene expression in two high-toothed stickleback populations
Authors: Hart James C. , Ellis Nicholas A. , Eisen Michael B. , Milller Craig T.
Published: February 2018

Changes in developmental gene regulatory networks enable evolved changes in morphology. These changes can be incisregulatory elements that act in an allele-specific manner, or changes to the overalltransregulatory environment that interacts withcisregulatory sequences. Here we address several questions about the evolution of gene expression accompanying a convergently evolved constructive morphological trait, increases in tooth number in two independently derived freshwater populations of threespine stickleback fish (Gasterosteus aculeatus). Are convergently evolvedcisand/ortranschanges in gene expression associated with convergently evolved morphological evolution? Docisortransregulatory changes contribute more to the evolutionary gain of a morphological trait? Transcriptome data from dental tissue of ancestral low-toothed and two independently derived high-toothed stickleback populations revealed significantly shared gene expression changes that have convergently evolved in the two high-toothed populations. Comparingcisandtransregulatory changes using phased gene expression data from F1 hybrids, we found thattransregulatory changes were predominant and more likely to be shared among both high-toothed populations. In contrast, whilecisregulatory changes have evolved in both high-toothed populations, overall these changes were distinct and not shared among high-toothed populations. Together these data suggest that a convergently evolved trait can occur through genetically distinct regulatory changes that converge on similartransregulatory environments.

Author Summary

Convergent evolution, where a similar trait evolves in different lineages, provides an opportunity to study the repeatability of evolution. Convergent morphological evolution has been well studied at multiple evolutionary time scales ranging from ancient, to recent, such as the gain in tooth number in freshwater stickleback fish. However, much less is known about the accompanying evolved changes in gene regulation during convergent evolution. Here we compared evolved changes in gene expression in dental tissue of ancestral low-toothed marine fish to fish from two independently derived high-toothed freshwater populations. We also partitioned gene expression changes into those affecting a gene’s regulatory elements (cis), and those affecting the overall regulatory environment (trans). Both freshwater populations have evolved similar gene expression changes, including a gain of expression of putative dental genes. These similar gene expression changes are due mainly to shared changes to thetransregulatory environment, while thecischanges are largely population specific. Thus, during convergent evolution, overall similar and perhaps predictable transcriptome changes can evolve despite largely different underlying genetic bases.
Investigating Protein-Protein Allosteric Network using Current-Flow Scheme
Authors: Botello-Smith Wesley M. , Luo Yun
Published: February 2018

Protein dynamic network analysis provides a powerful tool for investigating protein allosteric regulation. We recently developed a current-flow betweenness scheme for protein network analysis and demonstrated that this method, i.e. using current-flow betweenness as edge weights, is more appropriate and more robust for investigating the signal transmission between two predefined protein residues or domains as compared with direct usage of correlation scores as edge weights. Here we seek to expand the current-flow scheme to study allosteric regulations involving protein-protein binding. Specifically, we investigated three gain-of-function mutations located at the binding interface of ALK2 (also known as ACVR1) kinase and its inhibitory protein FKBP12. We first searched for the optimal smoothing function for contact network construction and then calculated the subnetwork between FKBP12 protein and ALK2 ATP binding site using current-flow betweenness. By comparing the networks between the wild-type and three mutants, we have identified statistically significant changes in the protein-protein networks that are common among all three mutants that allosterically shift the kinase towards a catalytically competent configuration.
Local adaptation primes cold-edge populations for range expansion but not warming-induced range shifts
Authors: Hargreaves Anna L. , Eckert Christopher G.
Published: February 2018

According to theory, edge populations may be the best suited to initiate range expansions and climate-driven range shifts if they are locally adapted to extreme edge conditions, or the worst suited to colonize beyond-range habitat if their offspring are genetically and competitively inferior. We tested these contrasting predictions by comparing fitness of low, mid, and high-elevation (edge) populations of the annualRhinanthus minor, transplanted throughout and above its elevational distribution under natural and experimentally-warmed conditions. Seed from low-quality edge habitat had inferior emergence across sites, but high-elevation seeds were also locally adapted. High-elevation plants initiated flowering earlier than plants from lower populations, required less heat accumulation to mature seed, and so achieved higher lifetime fitness at high elevations. Fitness was strongly reduced above the range, but adaptive phenology enhanced the relative fitness of high-elevation seeds. Experimental warming improved fitness above the range, confirming climate’s importance in limitingR. minor’s distribution, but eliminated the advantage of local cold-edge populations. These results provide experimental support for recent models in which cold-adapted edge populations do not always facilitate warming-induced range shifts. The highest fitness above the range was achieved by a ‘super edge phenotype’ from a neighboring mountain, suggesting key adaptations exist at the regional scale even if absent from local edge populations. Our results demonstrate that assessing the value of edge populations will not be straightforward, but suggest that a regional approach to their conservation, potentially enhancing gene flow among them, might maximize species’ ability to respond to global change.

Significance

Individuals from range-edge populations are the most likely to disperse to habitat beyond the species current range, but are they best suited to colonize it? Our multi-year transplant experiment throughout and above the elevational range of an annual herb in the Canadian Rocky Mountains found that adaptive flowering phenology enhanced the fitness of high-edge seeds above the range, outweighing detrimental effects of poor seed quality. However, only one edge population maintained its advantage over central populations under experimental warming. While edge populations were most likely to drive range expansion, adaptation to cold climates may not help them initiate range shifts in response to climate warming, unless superior genotypes spread among isolated edge populations.
Deep Convolutional Neural Networks for Breast Cancer Histology Image Analysis
Authors: Rakhlin Alexander , Shvets Alexey , Iglovikov Vladimir , Kalinin Alexandr A.
Published: February 2018

Breast cancer is one of the main causes of cancer death worldwide. Early diagnostics significantly increases the chances of correct treatment and survival, but this process is tedious and often leads to a disagreement between pathologists. Computer-aided diagnosis systems showed potential for improving the diagnostic accuracy. In this work, we develop the computational approach based on deep convolution neural networks for breast cancer histology image classification. Hematoxylin and eosin stained breast histology microscopy image dataset is provided as a part of the ICIAR 2018 Grand Challenge on Breast Cancer Histology Images. Our approach utilizes several deep neural network architectures and gradient boosted trees classifier. For 4-class classification task, we report 87.2% accuracy. For 2-class classification task to detect carcinomas we report 93.8% accuracy, AUC 97.3%, and sensitivity/specificity 96.5/88.0% at the high-sensitivity operating point. To our knowledge, this approach outperforms other common methods in automated histopathological image classification. The source code for our approach is made publicly available athttps://github.com/alexander-rakhlin/ICIAR2018
Endoderm Morphogenesis Reveals Integration of Distinct Processes in the Development and Evolution of Pharyngeal Arches
Authors: Okada Kazunori , Wada Hiroshi , Takada Shinji
Published: February 2018

The vertebrate pharyngeal arches (PAs) are established by a combination of two styles of segmentation; the most anterior 2 PAs are simultaneously but the others are sequentially formed. However, the mechanism underlying their coexistence is unclear. Here, we show that the simultaneous and sequential segmentation discretely proceeded, respectively, but were finally integrated at the second PP (PP2), by dynamic morphogenesis of pharyngeal endoderm in the zebrafish. The coordination of these 2 distinct processes appears to be common in the PA development of many vertebrates, in which specific developmental defects posterior to the PP2 are caused by mutations of particular genes or perturbation of retinoic acid signaling. Surprisingly, comparative analysis of PA segmentation showed that the combinatorial styles of PA development is present in shark but not in lamprey, suggesting that PA segmentation was modified in the stem gnathostomes corresponding to the drastic pharyngeal innovations, such as PA2-derived opercular.
Education can Reduce Health Disparities Related to Genetic Risk of Obesity: Evidence from a British Reform
Authors: Barcellos Silvia H. , Carvalho Leandro S. , Turley Patrick
Published: February 2018

This paper investigates whether genetic makeup moderates the effects of education on health. Low statistical power and endogenous measures of environment have been obstacles to the credible estimation of such gene-by-environment interactions. We overcome these obstacles by combining a natural experiment that generated variation in secondary education with polygenic scores for a quarter million individuals. The additional schooling affected body size, lung function, and blood pressure in middle age. The improvements in body size and lung function were larger for individuals with high genetic predisposition to obesity. As a result, education reduced the gap in unhealthy body size between those with high and low genetic risk of obesity from 20 to 6 percentage points.
Ximmer: A System for Improving Accuracy and Consistency of CNV Calling from Exome Data
Authors: Sadedin Simon P , Ellis Justine A , Masters Seth L , Oshlack Alicia
Published: February 2018

Detection of copy number variation (CNVs) is a challenging but highly valuable application of exome and targeted high throughput sequencing (HTS) data. While there are dozens of CNV detection methods available, using these methods remains challenging due to variable accuracy both across different data sets and within the same data set with different methods. We propose that extracting good results from CNV detection on HTS data requires a systematic approach involving rigorous quality control, adjustment of method parameters and calibration of confidence measures for filtering results. We present Ximmer, a tool which supports an end to end process for applying these procedures including a simulation framework, CNV detection analysis pipeline, and a visualisation and curation tool which enables interactive exploration of CNV results. We apply Ximmer to perform a comprehensive evaluation of CNV detection on four data sets using four different detection methods, representing one of the most comprehensive evaluations to date. Ximmer is open source and freely available at http://ximmer.org (example results are viewable at http://example.ximmer.org).
Non-invasive Assessment of Liver Disease in Rats Using Multiparametric Magnetic Resonance Imaging: A Feasibility Study
Authors: Hoy Anna M. , McDonald Natasha , Lennen Ross J. , Milanesi Matteo , Herlihy Amy H. , Kendall Timothy J. , Mungall William , Gyngell Michael , Banerjee Rajarshi , Janiczek Robert L. , Murphy Philip S. , Jansen Maurits A. , Fallowfield Jonathan A.
Published: February 2018

Background & Aims

Non-invasive quantitation of chronic liver disease using multiparametric MRI has the potential to refine clinical care pathways, trial design and preclinical drug development. The aim of the study was to evaluate the use of multiparametric liver MRI in experimental rat models of chronic liver disease.Methods: Liver injury was induced in male wild-type Sprague-Dawley rats using 4 or 12 weeks carbon tetrachloride (CCl4) intoxication and 4 or 8 weeks methionine and choline deficient (MCD) diet. Liver MRI was performed using a 7.0 Tesla small animal scanner at baseline and specified timepoints after liver injury. Multiparametric liver MRI parameters (T1 mapping, T2* mapping and proton density fat fraction (PDFF)) were correlated with gold standard histopathological measures, assessed by a blinded expert adjudicator. One-way analysis of variance with Tukey’s post-hoc test was used to assess differences between groups and Spearman’s rank-order correlation to examine associations.

Results

Mean hepatic T1 increased significantly in rats treated with CCl4for 12 weeks compared to controls (1122±78 ms vs. 959±114 ms; d=162.7, 95% CI (11.92, 313.4),P=0.038) and correlated strongly with histological collagen content (rs=0.717,P=0.037). In MCD diet-treated rats, hepatic PDFF correlated strongly with histological fat content (rs=0.819,P<0.0001), steatosis grade (rs=0.850,P<0.0001) and steatohepatitis score (rs=0.818,P<0.0001). Although there was minimal histological iron, progressive fat accumulation in MCD diet-treated liver significantly shortened T2*.

Conclusions

In preclinical models, quantitative MRI markers correlated with histopathological assessments, especially for fatty liver disease. Validation in longitudinal studies is required.

Key points

Non-invasive quantitative measures of chronic liver injury are needed for stratification and monitoring of disease in clinical practice and in drug development

We adapted and applied a clinically-relevant non-contrast multiparametric MRI protocol in well-established preclinical liver disease models, for simultaneous quantitation of hepatic fat, fibro-inflammatory injury and iron

Multiparametric liver MRI was feasible at 7.0 Tesla in experimental rat models and imaging parameters correlated with gold standard histopathological assessments, especially characteristics of fatty liver disease

Further development of multiparametric liver MRI could refine drug development strategies and impact upon trial design and clinical care pathways
A new, phenotypically distinct subpopulation of Regulatory Killer T ex-Th17 cells expressing CD4lowCD25hiCD49hiFoxp3hiRORlowIL-17low
Authors: Sayapina Maria S.
Published: February 2018

Th17 and regulatory T (Treg) cells are integral in maintaining immune homeostasis and Th17– Treg imbalance is associated with inflammatory immunosuppression in cancer. Here it is shown that in addition to ROR+Foxp3+ cells eTreg cells are a source of ex-Th17 CD4lowCD25hiCD49hiFoxp3hi (Regulatory Killer T – RKT) cells while the latest are much more suppressive. Moreover, we have identified a set of key cytokines that favor the generation and expansion ex-Th17 Foxp3low cells. These findings should accelerate efforts to define the function of this new subset of Treg cells in the immune response to cancer.
psichomics: graphical application for alternative splicing quantification and analysis
Authors: Saraiva-Agostinho Nuno , Barbosa-Morais Nuno L.
Published: February 2018

Alternative pre-mRNA splicing generates functionally distinct transcripts from the same gene and is involved in the control of multiple cellular processes, with its dysregulation being associated with a variety of pathologies. The advent of next-generation sequencing has enabled global studies of alternative splicing in different physiological and disease contexts. However, current bioinformatics tools for alternative splicing analysis from RNA-seq data are not user-friendly, disregard available exon-exon junction quantification or have limited downstream analysis features. To overcome such limitations, we have developedpsichomics, an R package with an intuitive graphical interface for alternative splicing quantification and downstream dimensionality reduction, differential splicing and gene expression and survival analyses based on The Cancer Genome Atlas, the Genotype-Tissue Expression project and user-provided data. These integrative analyses can also incorporate clinical and molecular sample-associated features. We successfully usedpsichomicsto reveal alternative splicing signatures specific to stage I breast cancer and associated novel putative prognostic factors.
Mammalian Cells Engineered to Produce Novel Steroids
Authors: Spady Emma S. , Wyche Thomas P. , Rollins Nathanael J. , Clardy Jon , Way Jeffrey C. , Silver Pamela A.
Published: February 2018

Steroids can be difficult to modify via traditional organic synthesis methods, but many enzymes regio- and stereo-selectively process a wide variety of steroid substrates. We tested whether steroid-modifying enzymes could make novel steroids from non-native substrates. Numerous genes encoding steroid-modifying enzymes, including some bacterial enzymes, were expressed in mammalian cells by transient transfection and found to be active. We made three unusual steroids by expression in HEK293 cells of the 7α-hydroxylase CYP7B1, which was selected because of high native product yield. These cells made 7α,17α-dihydroxypregnenolone and 7β,17α-dihydroxypregnenolone from 17α-hydroxypregnenolone, and produced 11α,16α-dihydroxyprogesterone from 16α-hydroxyprogesterone. The latter two products resulted from previously unobserved CYP7B1 hydroxylation sites. A Rosetta docking model of CYP7B1 suggested that these substrates’ D-ring hydroxylations may prevent them from binding in the same way as the native substrate, bringing different carbons near the active ferryl oxygen. This new approach could use other enzymes and substrates to produce many novel steroids for drug candidate testing.
Regulation of cyclic electron flow by chloroplast NADPH-dependent thioredoxin system
Authors: Nikkanen Lauri , Toivola Jouni , Trotta Andrea , Guinea Diaz Manuel , Tikkanen Mikko , Aro Eva-Mari , Rintamäki Eevi
Published: February 2018

Linear electron transport in the thylakoid membrane drives both photosynthetic NADPH and ATP production, while cyclic electron flow (CEF) around photosystem I only promotes the translocation of protons from stroma to thylakoid lumen. The chloroplast NADH-dehydrogenase-like complex (NDH) participates in one CEF route transferring electrons from ferredoxin back to the plastoquinone pool with concomitant proton pumping to the lumen. CEF has been proposed to balance the ratio of ATP/NADPH production and to control the redox poise particularly in fluctuating light conditions, but the mechanisms regulating the NDH complex remain unknown. We have investigated potential regulation of the CEF pathways by the chloroplast NADPH-thioredoxin reductase (NTRC)in vivoby using an Arabidopsis knockout line ofNTRCas well as lines overexpressing NTRC. Here we present biochemical and biophysical evidence showing that NTRC activates the NDH-dependent CEF and regulates the generation of proton motive force, thylakoid conductivity to protons and redox balance between the thylakoid electron transfer chain and the stroma during changes in light conditions. Further, protein–protein interaction assays suggest a putative thioredoxin-target site in close proximity to the ferredoxin binding domain of NDH, thus providing a plausible mechanism for regulation of the NDH ferredoxin:plastoquinone oxidoreductase activity by NTRC.

One sentence summary

Chloroplast thioredoxins regulate photosynthetic cyclic electron flow that balances the activities of light and carbon fixation reactions and improves plant fitness under fluctuating light conditions.
Speed Regulation and Gradual Enhancer Switching Models as Flexible and Evolvable Patterning Mechanisms
Authors: Kuhlmann Lukas , El-Sherif Ezzat
Published: February 2018

Short Abstract

Using simple animations, mathematical formulations, and computational implementation in Matlab, we present a newly devised embryonic patterning mechanism: the Speed Regulation model, and its molecular realization: the Gradual Enhancer Switching model. We show how our models shed light on the phenomenology of insect development and evolution.

Long Abstract

Partitioning an initially homogeneous group of cells into different fates is a common problem in development. A curious case is the anterior-posterior (AP) fate specification during early embryogenesis in insects. The AP fates of most insects are specified in two different phases: (i) the blastoderm, where the AP axis does not undergo any axial elongation, and (ii) the germband, where the AP axis undergoes gradual axis elongation. Throughout evolution, insects show remarkable flexibility in the number of fates specified in the blastoderm vs germband. This hints that AP specification in insects relies on a flexible mechanism that can pattern both non-elongating embryonic structures (like the blastoderm) and elongating tissues (like the germband). Here we describe the ‘Speed Regulation’ model, a recently suggested patterning mechanism, that can pattern both elongating and non-elongating tissues and ensures the evolvability between them. The model is successful in reproducing the phenomenology of AP axis specification and evolution in insects. In addition, it explains the temporal-based patterning of other embryonic structures like the AP axis of vertebrates and the dorsoventral axis of vertebrate neural tube. The Speed Regulation model is phenomenological in its formulation, in the sense that it does not specify a particular molecular realization. We then present the ‘Gradual Enhancer Switching’ model, in which we describe a specific molecular implementation of the Speed Gradient model that incorporates a novel scheme of cis-regulation within gene regulatory networks. The paper is linked to two videos on YouTube referred to below.

Linked Videos

Video I: https://youtu.be/YcGotl8OdYw

Video II: https://youtu.be/f-JnjF2aNLw
Competent for commitment: you've got to have heart!
Authors: Jain Rajan , Epstein Jonathan A.
Published: February 2018

The mature heart is composed primarily of four different cell types: cardiac myocytes, endothelium, smooth muscle, and fibroblasts. These cell types derive from pluripotent progenitors that become progressively restricted with regard to lineage potential, giving rise to multipotent cardiac progenitor cells and, ultimately, the differentiated cell types of the heart. Recent studies have begun to shed light on the defining characteristics of the intermediary cell types that exist transiently during this developmental process and the extrinsic and cell-autonomous factors that influence cardiac lineage decisions and cellular competence. This information will shape our understanding of congenital and adult cardiac disease and guide regenerative therapeutic approaches. In addition, cardiac progenitor specification can serve as a model for understanding basic mechanisms regulating the acquisition of cellular identity. In this review, we present the concept of “chromatin competence” that describes the potential for three-dimensional chromatin organization to function as the molecular underpinning of the ability of a progenitor cell to respond to inductive lineage cues and summarize recent studies advancing our understanding of cardiac cell specification, gene regulation, and chromatin organization and how they impact cardiac development.
Political connections and audit report lag: Indonesian evidence
Authors: Habib Ahsan , Muhammadi Abdul Haris
Published: February 2018

Purpose

This paper aims to investigate the association between political connections and the audit report lag and whether related party transactions moderate the association between the two.

Design/methodology/approach

An ordinary least square regression is estimated whereby audit report lag is regressed on political connections, related party transactions and the interaction between the two. Data on the number and amounts of RPTs are hand-collected from audited financial reports. A firm-year observation is politically connected if at least one large shareholder (controlling at least 10 per cent of the votes directly or indirectly) or board member or commissioner is a current or former Member of Parliament, a minister or head of local government or closely related to a politician or party.

Findings

Findings show that the audit report lag is relatively short for politically connected firms but increases when such firms conduct both operating and loan-type related party transactions. This suggests that auditors understand the incentives for, and the implications of, related party transactions and hence exert additional audit efforts in scrutinizing financial statements: activities that will increase the audit report lag.

Originality/value

Although a large body of empirical research exists on the determinants of audit report lag, none has examined the impact of political connections. This paper further contributes to the auditing literature by documenting auditors’ evaluation of related party transactions in a developing country.
Moderating role of religiosity on Zakat compliance behavior in Nigeria
Authors: Farouk Abubakar U. , Md Idris Kamil , Saad Ram Al Jaffri Bin
Published: February 2018

Purpose

This paper examines the moderating effect of religiosity in the theory of reasoned action (TRA) on intention to comply with the Zakat on employment income (ZEI).

Design/methodology/approach

A survey of civil servants in Kano State, Nigeria was carried out and 474 valid observations were retrieved from the 700 distributed questionnaires. Partial least squares structural equation modeling (PLS-SEM) was used to validate the instrument that measures the variables, examined the structural model and the predictive relevance of the study’s model.

Findings

The results revealed the suitability of both the TRA and the PLS-SEM in the study of ZEI behavioral intention in a developing country. All the hypothesized direct relationships were supported on the one hand. On the other hand, one of the two indirect relationships, subjective norm and behavioral intention moderated by religiosity was supported, but the other tests for moderating effects of religiosity on the relationship between attitude and behavioral intention was not.

Practical implications

Public and private Zakat institutions in Muslim majority societies in Nigeria and in other Muslim countries may use the findings to focus their attention on the formulation of policies based on the findings of the study to strengthen eligible Zakat payers’ intention to comply to further boost their Zakat collections.

Originality/value

This study extends the TRA in the context of ZEI by proposing religiosity as a moderator in the predictive capacity of TRA on ZEI. Moreover, the suitability for the use of PLS-SEM as a statistical tool in investigating the extended TRA with religiosity as a moderating variable as well as its implications for theory and practice were also discussed.
Development and validation of health service management competencies
Authors: Liang Zhanming , Howard Peter F. , Leggat Sandra , Bartram Timothy
Published: February 2018

Purpose

The importance of managerial competencies in monitoring and improving the performance of organisational leaders and managers is well accepted. Different processes have been used to identify and develop competency frameworks or models for healthcare managers around the world to meet different contextual needs. The purpose of the paper is to introduce a validated process in management competency identification and development applied in Australia – a process leading to a management competency framework with associated behavioural items that can be used to measure core management competencies of health service managers.

Design/methodology/approach

The management competency framework development study incorporated both qualitative and quantitative methods, implemented in four stages, including job description analysis, focus group discussions and online surveys.

Findings

The study confirmed that the four-stage process could identify management competencies and the framework developed is considered reliable and valid for developing a management competency assessment tool that can measure management competence amongst managers in health organisations. In addition, supervisors of health service managers could use the framework to distinguish perceived superior and average performers among managers in health organisations.

Practical implications

Developing the core competencies of health service managers is important for management performance improvement and talent management. The six core management competencies identified can be used to guide the design professional development activities for health service managers.

Originality/value

The validated management competency identification and development process can be applied in other countries and different industrial contexts to identify core management competency requirements.
A decision-making model to support the design of a strategic supply chain configuration
Authors: Song Guang , Sun Luoyi , Wang Yixiao
Published: February 2018

Purpose

The purpose of this paper is to apply an empirically based approach to develop a decision-making model that comprehensively incorporates the potential affecting factors and the related significant drivers that support network designers in selecting the appropriate strategic supply chain configuration or checking the coherence of an existing supply chain structure in four industry sectors.

Design/methodology/approach

The decision-making model is developed based on an empirical study that integrates multiple case studies and statistical analyses. In total, 113 best-in-class manufacturing firms in four sectors are studied to investigate their strategic supply chain configurations and the information of identified affecting drivers. The factor analysis and regression analysis are conducted to classify the drivers into five factor groups, and to identify the significant drivers used to develop the decision-making model.

Findings

The findings of this research are three-pronged. First, 12 significant drivers related to 5 factor groups affecting strategic supply chain network design (SCND) are identified. Second, a decision-making model is developed to support users in strategic SCND. Last, the main characteristics of various strategic supply chain configurations are summarized in four industry sectors.

Research limitations/implications

The authors identified valuable insights for both academics and practitioners based on the identified significant affecting drivers and the developed decision-making model. In addition, this study also proposes two potential research lines on the study of additional contextual affecting factors and decision issues in strategic SCND.

Originality/value

This study could be the first attempt to use an empirically based method to develop a decision-making model aimed at supporting the preliminary design of a supply chain network. Therefore, the drawbacks of a pure qualitative conceptual model and optimization model are eliminated.
Consequences of customer engagement and customer self-brand connection
Authors: Moliner Miguel Ángel , Monferrer-Tirado Diego , Estrada-Guillén Marta
Published: February 2018

Purpose

The purpose of this paper is to analyze the impact of the customer engagement and customer self-brand connection on customer advocacy and firms’ financial performance. The research focuses on the financial sector and studies a complex organization with a uniform strategy, but which attends the public in different centers (bank branches).

Design/methodology/approach

A theoretical model of effects is tested using dyadic methodology, with 225 dyads (bank branch manager – average of five customers). The authors use structural equation modeling (EQS6.1) to test the relationships.

Findings

The results corroborate the hypotheses, with the exception of the influence of customer self-brand connection on financial performance. These analyses show that in the banking sector, where the intensive use of new information and technologies has led to a reduction in direct physical contact with the customer, the off-line experience continues to have a notable economic impact. Furthermore, investment in the brand from an experiential approach determines customer advocacy.

Originality/value

The contribution of this paper is twofold. This research analyzes from a theoretical and empirical perspective the impact of the customer engagement and customer self-brand connection on customer advocacy and firms’ financial performance.
Crisis decision-making: the overlap between intuitive and analytical strategies
Authors: Okoli Justin , Watt John
Published: February 2018

Purpose

The purpose of this paper is to draw on the naturalistic decision making and cognitive science literature to examine how experienced crisis managers utilize the intuitive and analytical strategies when managing complex incidents. A cognitive model that describes the interplay between strategies is presented and discussed, and the specific role that intuition plays in analytical decision making is addressed.

Design/methodology/approach

Designed as a conceptual paper, the extant literature is reviewed to advance discussions on the theme of intuitive and analytical decision making in the naturalistic environment. A new model of expert intuition – the information filtering and intuitive decision model – is presented and evaluated against existing cognitive models from the wider literature.

Findings

The paper suggests that experts’ ability to make intuitive decisions is strongly hinged on their information processing skills that allow irrelevant cues to be sifted out while the relevant cues are retained. The paper further revealed that experts generally employ the intuitive mode as their default strategy, drawing on the analytical mode only as conditions warrant.

Originality/value

Prior research has shown that experts often make important task decisions using intuitive or analytical strategies or by combining both, but the sequence these should typically follow is still unresolved. Findings from the intuition model reveal that although intuition often precedes analytical thinking in almost all cases, both strategies exist to offer significant values to decision makers if the basis of their application is well understood.
Social business as an entrepreneurship model in emerging economy
Authors: Mahfuz Ashraf Md , Razzaque Mohammed Abdur , Liaw Siaw-Teng , Ray Pradeep Kumar , Hasan Md Rashadul
Published: February 2018

Purpose

Despite its immense potentials as a sustainable and innovative means to solve specific social problems, the basic concept of the social business model (SBM) advanced by Professor Muhammad Yunus remains unclear to many. There exists no literature that objectively compares this model from empowerment and economic growth perspectives with other seemingly similar concepts, such as social enterprise, non-governmental organization (NGO) and corporate social responsibility. Although many NGOs have been showing increasing interest towards the adoption of the SBM to minimize social problems sustainably, lack of conceptual clarity of the model limits the scope of its adoption in addressing social issues. The paper aims to discuss these issues.

Design/methodology/approach

This study is based on a systematic search, analysis and review of literature. It has made use of narrative synthesis of relevant literature on a diverse range of socially oriented models, frameworks and interventions.

Findings

This study identified five key aspects of social business, namely: business’s mission and outcomes, characteristics, operation, resource utilization and environmental considerations. Based on these five key aspects one may like to infer that unlike other social interventions, the alignment of SBM is specific to empowerment of disadvantaged people leading to sustainable economic growth. Analyzing a range of social business interventions in a developing country, Bangladesh, through the lens five key aspects demonstrates that social business is the most efficient way to sustainably maximize the social benefits and minimize specific social issues poverty of the people affected.

Originality/value

This study discusses the scopes of adopting SBM for the socially responsible organizations for sustainable empowerment and economic growth in emerging economies.