bluuebunny/crossref_metadata_2025 huggingface dataset:
Internalization of erythrocyte acylpeptide hydrolase is required for asexual replication ofPlasmodium falciparum
Authors: Elahi Rubayet , Dapper Christie , Klemba Michael
Published: February 2019

The human malaria parasitePlasmodium falciparumcauses disease as it replicates within the host’s erythrocytes. We have found that an erythrocyte serine hydrolase, acylpeptide hydrolase (APEH), accumulates within developing asexual parasites. Internalization of APEH was associated with a proteolytic event that reduced the size of the catalytic polypeptide from 80 to 55 kDa, which suggests that the enzyme resides in the food vacuole. A triazole urea APEH inhibitor, termed AA74-1, was employed to characterize the role of parasite-internalized APEH.In vitro, AA74-1 was a potent and highly selective inhibitor of both host erythrocyte and parasite-internalized APEH. When added to cultures of parasite-infected erythrocytes, AA74-1 was a relatively poor inhibitor of replication over one asexual replication cycle; however, its potency increased dramatically after a second cycle. This enhancement of potency was not abrogated by the addition of exogenous isopentenyl pyrophosphate, which distinguishes it from the well-characterized “delayed death” phenomenon that is observed with inhibitors that target the parasite apicoplast. Analysis of inhibition by AA74-1in vivorevealed that a concentration of 100 nM was sufficient to quantitatively inhibit erythrocyte APEH. In contrast, the parasite-internalized APEH pool was inefficiently inhibited at concentrations up to 100-fold higher. Together, these findings provide evidence for an essential catalytic role for parasite-internalized APEH and suggest a model for AA74-1 growth inhibition whereby depletion of parasite APEH activity requires the internalization of inactive host cell APEH over two replication cycles.

IMPORTANCE

Nearly half a million deaths were attributed to malaria in 2017. Protozoan parasites of the genusPlasmodiumcause disease in humans while replicating asexually within the host’s erythrocytes, withP. falciparumresponsible for most of the mortality. Understanding howPlasmodiumspp. has adapted to its unique host erythrocyte environment is important for developing malaria control strategies. Here, we demonstrate thatP. falciparumco-opts a host erythrocyte serine hydrolase termed acylpeptide hydrolase. By showing that the parasite requires acylpeptide hydrolase activity for replication, we expand our knowledge of host cell factors that contribute to robust parasite growth.
Formal axioms in biomedical ontologies improve analysis and interpretation of associated data
Authors: Smaili Fatima Zohra , Gao Xin , Hoehndorf Robert
Published: February 2019

Motivation

There are now over 500 ontologies in the life sciences. Over the past years, significant resources have been invested into formalizing these biomedical ontologies. Formal axioms in ontologies have been developed and used to detect and ensure ontology consistency, find unsatisfiable classes, improve interoperability, guide ontology extension through the application of axiom-based design patterns, and encode domain background knowledge. At the same time, ontologies have extended their amount of human-readable information such as labels and definitions as well as other meta-data. As a consequence, biomedical ontologies now form large formalized domain knowledge bases and have a potential to improve ontology-based data analysis by providing background knowledge and relations between biological entities that are not otherwise connected.

Results

We evaluate the contribution of formal axioms and ontology meta-data to the ontology-based prediction of protein-protein interactions and gene–disease associations. We find that the formal axioms that have been created for the Gene Ontology and several other ontologies significantly improve ontology-based prediction models through provision of domain-specific background knowledge. Furthermore, we find that the labels, synonyms and definitions in ontologies can also provide background knowledge that may be exploited for prediction. The axioms and meta-data of different ontologies contribute in varying degrees to improving data analysis. Our results have major implications on the further development of formal knowledge bases and ontologies in the life sciences, in particular as machine learning methods are more frequently being applied. Our findings clearly motivate the need for further development, and the systematic, application-driven evaluation and improvement, of formal axioms in ontologies.

Availability

https://github.com/bio-ontology-research-group/tsoe

Contact

robert.hoehndorf@kaust.edu.sa, xin.gao@kaust.edu.sa
Profiling embryonic stem cell differentiation by MALDI-MS: development of a reproducible and robust sample preparation workflow
Authors: Heap Rachel E. , Segarra-Fas Anna , Findlay Greg M. , Trost Matthias
Published: February 2019

MALDI-TOF mass spectrometry (MS) is widely used to characterize and biotype bacterial samples, but a complimentary method for profiling of mammalian cells is still underdeveloped. Current approaches vary dramatically in their sample preparation methods and are not suitable for high-throughput studies. In this work, we present a universal workflow for mammalian cell MALDI-TOF MS analysis and apply it to distinguish ground-state naïve and differentiating mouse embryonic stem cells (mESCs), which can be used as a model for drug discovery. We employed a systematic approach testing many parameters to evaluate how efficiently and reproducibly each method extracted unique mass features from four different human cell lines. This data enabled us to develop a unique mammalian cell MALDI-TOF workflow involving a freeze-thaw cycle, methanol fixing and CHCA matrix to generate spectra that yield maximum information and are highly reproducible. We applied our optimized workflow to distinguish naïve and differentiating populations using multivariate analysis and reproducibly identifying unique features. Consequently, our MALDI-TOF MS profiling method enables identification of unique biomarkers and robust phenotyping of mESC differentiation. This method can in the future be applied to profile other cell types and expanded towards cellular MALDI-TOF MS screening assays.
Predicting educational achievement from genomic measures and socioeconomic status
Authors: von Stumm Sophie , Smith-Woolley Emily , Ayorech Ziada , McMillan Andrew , Rimfeld Kaili , Dale Philip S. , Plomin Robert
Published: February 2019

The two best predictors of children’s educational achievement available from birth are parents’ socioeconomic status (SES) and, recently, children’s inherited DNA differences that can be aggregated in genome-wide polygenic scores (GPS). Here we chart for the first time the developmental interplay between these two predictors of educational achievement at ages 7, 11, 14 and 16 in a sample of almost 5,000 UK school children. We show that the prediction of educational achievement from both GPS and SES increases steadily throughout the school years. Using latent growth curve models, we find that GPS and SES not only predict educational achievement in the first grade but they also account for systematic changes in achievement across the school years. At the end of compulsory education at age 16, GPS and SES respectively predict 14% and 23% of the variance of educational achievement; controlling for genetic influence on SES reduces its predictive power to 16%. Analyses of the extremes of GPS and SES highlight their influence and interplay: In children who have high GPS and come from high SES families, 77% go to university, whereas 21% of children with low GPS and from low SES backgrounds attend university. We find that the effects of GPS and SES are primarily additive, suggesting that their joint impact is particularly dramatic for children at the extreme ends of the distribution.
Reconstructing and Analysing The Genome of The Last Eukaryote Common Ancestor to Better Understand the Transition from FECA to LECA
Authors: Newman David , Whelan Fiona J. , Moore Matthew , Rusilowicz Martin , McInerney James O.
Published: February 2019

It is still a matter of debate whether the First Eukaryote Common Ancestor (FECA) arose from the merger of an archaeal host with an alphaproteobacterium, or was a proto-eukaryote with significant eukaryotic characteristics way before endosymbiosis occurred. The Last Eukaryote Common Ancestor (LECA) as its descendant is thought to be an entity that possessed functional and cellular complexity comparable to modern organisms. The precise nature and physiology of both of these organisms has been a long-standing, unanswered question in evolutionary and cell biology. Recently, a much broader diversity of eukaryotic genomes has become available and this means we can reconstruct early eukaryote evolution with a greater deal of precision. Here, we reconstruct a hypothetical genome for LECA from modern eukaryote genomes. The constituent genes were mapped onto 454 pathways from the KEGG database covering cellular, genetic, and metabolic processes across six model species to provide functional insights into it’s capabilities. We reconstruct a LECA that was a facultatively anaerobic, single-celled organism, similar to a modern Protist possessing complex predatory and sexual behaviour. We go on to examine how much of these capabilities arose along the FECA-to-LECA transition period. We see a at least 1,554 genes gained by FECA during this evolutionary period with extensive remodelling of pathways relating to lipid metabolism, cellular processes, genetic information processing, protein processing, and signalling. We extracted the BRITE classifications for the genes from the KEGG database, which arose during the transition from FECA-to-LECA and examine the types of genes that saw the most gains and what novel classifications were introduced. Two-thirds of our reconstructed LECA genome appears to be prokaryote in origin and the remaining third consists of genes with functional classifications that originate from prokaryote homologs in our LECA genome. Signal transduction and Post Translational Modification elements stand out as the primary novel classes of genes developed during this period. These results suggest that largely the eukaryote common ancestors achieved the defining characteristics of modern eukaryotes by primarily expanding on prokaryote biology and gene families.
Donor-Free Gene Correction by Targeted Interhomolog Recombination
Authors: Davis Luther , Khoo Kevin J. , Maizels Nancy
Published: February 2019

Spontaneous gene correction by interhomolog recombination (IHR) occasionally occurs to ameliorate genetic diseases of blood and skin1–3. Using an engineered endogenous gene as a reporter, we demonstrate that gene correction by IHR is normally infrequent (≤0.02%) but is stimulated by DSBs targeted by CRISPR/Cas9 to both homologous chromosomes; reaching frequencies of 0.5%. We further show that depletion of POLQ stimulates IHR frequencies 4-fold, to 2%, and promotes IHR in G2 phase, when recombination between replicated homologs can correct not only compound heterozygous but also autosomal dominant “gain-of-function” mutations, which present a special challenge for gene therapy. The strategies reported here will enable optimization of IHR for gene therapy in a variety of cell types. Advantages include the ability to correct gain-of-function mutations, no need for an exogenous donor, and the potential to limit damage to coding sequence by targeting IHR to introns.
Assessment of the effects of aerobic fitness on cerebrovascular function in young adults using multiple inversion time arterial spin labelling MRI
Authors: Foster Catherine , Steventon Jessica J , Helme Daniel , Tomassini Valentina , Wise Richard G.
Published: February 2019

The cross-sectional study investigated the effects of aerobic fitness on cerebrovascular function in the healthy brain. We quantified grey matter (GM) cerebral blood flow (CBF) and cerebrovascular reactivity (CVR), in a sample of young adults within a normal fitness range. Based on existing TCD and fMRI evidence, we predicted a positive relationship between fitness and resting GM CBF, and CVR. Exploratory hypotheses that higher peak would be associated with higher GM volume and cognitive performance were also investigated.

20 adults underwent a peak test and a battery of cognitive tests. All subjects underwent an MRI scan where multiple inversion time (MTI) pulsed arterial spin labelling (PASL) was used to quantify resting CBF and CVR to 5% CO2.

ROI analysis showed a non-significant negative correlation between whole-brain GM CBF and peak; r=-0.4, p=0.08, corrected p (p’) =0.16 and a significant positive correlation between peak and voxelwise whole-brain GM CVR; r=0.62, p=0.003, p’ =0.006. Voxelwise analysis revealed a significant inverse association between peak and resting CBF in the left and right thalamus, brainstem, right lateral occipital cortex, left intracalcarine cortex and cerebellum. The results of this study suggest that aerobic fitness is associated with lower CBF and greater CVR in young adults.
Episodic diversifying selection and intragenomic interactions shape the evolution of DNA and RNA viruses
Authors: Aris-Brosou Stéphane , Parent Louis , Ibeh Neke
Published: February 2019

Viruses are known to have some of the highest and most diverse mutation rates found in any biological replicator, topped by single-stranded (ss) RNA viruses, while double-stranded (ds) DNA viruses have rates approaching those of bacteria. As mutation rates are tightly and negatively correlated with genome size, selection is a clear driver of viral evolution. However, the role of intragenomic interactions as drivers of viral evolution is less well documented. To understand how these two processes affect viral evolution, we systematically surveyed ssRNA, ssDNA, dsRNA, and dsDNA viruses, to find which virus type and which functions show evidence for episodic diversifying selection and correlated evolution. We show that while evidence for selection is mostly found in single stranded viruses, and correlated evolution is more prevalent in DNA viruses, the genes that are affected by both processes are involved in key aspects of their life cycle, favoring viral stability over proliferation. We further show that both evolutionary processes are intimately linked at the amino acid level, which suggests that selection alone does not explain the whole evolutionary —and epidemiological— potential of viruses.
Ancient hybridization and introgression of an invadolysin gene in schistosome parasites
Authors: Platt Roy N. , McDew-White Marina , Clec’h Winka Le , Chevalier Frederic D. , Allan Fiona , Emery Aidan M. , Garba Amadou , Hamidou Amina A. , Ame Shaali M. , Webster Joanne P. , Rollinson David , Webster Bonnie L. , Anderson Timothy J. C.
Published: February 2019

The parasitic blood flukeSchistosoma haematobiumcauses urogenital schistosomiasis in humans and is a major cause of morbidity and mortality across sub-Saharan Africa.S. haematobiumhybridizes with livestock schistosomes, including S.bovis, however the frequency, direction, age and genomic consequences of hybridization are unknown. We sequenced 96S. haematobiumexomes from Niger and the Zanzibar archipelago. and found evidence of an ancient, introgression event between NigerienS. haematobiumandS. bovisoccurring 108-613 generations ago. Between 3.3-8.2% of NigerienS. haematobiumgenomes are derived fromS. bovisalleles, some of which show signatures of directional selection; the strongest signal spans a single gene in the invadolysin gene family, an M8 metalloprotease associated with parasitic life-history traits.
CAN TRANSCRANIAL DIRECT CURRENT STIMULATION OVER THE DORSOLATERAL PREFRONTAL CORTEX ENHANCE PROPRIOCEPTION?
Authors: Beck Eric N. , Narayanan Sankirtana Shankar , McDermott Rian , Witney Alice G.
Published: February 2019

Introduction

Proprioception (perception of one’s limb position) is critical for accurate and consistent movement, and is processed by the sensorimotor cortex. Increased prefrontal activity is associated with improved proprioception and motor performance. Anodal transcranial direct current stimulation (tDCS) of the left dorsolateral prefrontal cortex (DLPFC) has been found to increase activity of the sensorimotor cortex. Thus, this study aimed to investigate whether anodal tDCS of the DLPFC may enhance proprioception measured with a target task. It was hypothesized that tDCS over the left DLPFC would improve motor performance (error and variability) on a target task completed without vision.

Design

Single blind, within-participant, sham-controlled trial.

Methods

Fifteen healthy young adults (M:F=6:9, age=23.3 years) completed 18 trials of a computerized target task (manipulating a mouse) with their non-dominant upper-limb, with and without vision, before and after (pre/post assessment) 20-minutes of stimulation (anodal tDCS of the left DLPFC) and sham conditions. Averages and coefficient of variation (CV, variability between trials) of spatio-temporal parameters associated with the movement were measured. Stimulation/ sham sessions were counterbalanced (stimulation first session, n=8), with each session separated by one week. Repeated-measures ANOVA and pairwise comparisons (95% confidence intervals [CI]) were conducted.

Results

Regarding distance travelled CV, a significant interaction between condition and assessment (F(1,14)=5.09, p=0.041) demonstrated that variability was significantly less post-stimulation compared to pre (p=0.003). A significant interaction between assessment and vision (F(1,14)=30.08, p<0.001) regarding distance travelled CV showed that without vision, variability was significantly less at post compared to pre (p<0.001), and this decrease was found after the stimulation condition only (95% CI = Δ 7.4 +/− 1.6 [4.0 to 10.9]).

Conclusion

Since variability of distance travelled during the target task without vision was lower post-stimulation compared to pre, consistency of movement without vision, and therefore proprioception, may have been enhanced by anodal tDCS of the DLPFC. This improvement could be due to modulation of fronto-striatal-thalamic circuits. These findings may be the first step in developing tDCS methods as an effective adjunct therapy for dysfunctional proprioception in various disorders, such as Parkinson’s disease.
Ecological origins of perceptual grouping principles in the auditory system
Authors: Młynarski Wiktor , McDermott Josh H.
Published: February 2019

Events and objects in the world must be inferred from sensory signals to support behavior. Because sensory measurements are temporally and spatially local, the estimation of an object or event can be viewed as the grouping of these measurements into representations of their common causes. Per-ceptual grouping is believed to reflect internalized regularities of the natural environment, yet grouping cues have traditionally been identified using informal observation, and investigated using artificial stim-uli. The relationship of grouping to natural signal statistics has thus remained unclear, and additional or alternative cues remain possible. Here we derive auditory grouping cues by measuring and summarizing statistics of natural sound features. Feature co-occurrence statistics reproduced established cues but also revealed previously unappreciated grouping principles. The results suggest that auditory grouping is adapted to natural stimulus statistics, show how these statistics can reveal novel grouping phenomena, and provide a framework for studying grouping in natural signals.
Scalable and Accurate Drug–target Prediction Based on Heterogeneous Bio-linked Network Mining
Authors: Zong Nansu , Wong Rachael Sze Nga , Ngo Victoria , Yu Yue , Li Ning
Published: February 2019

Motivation

Despite the existing classification- and inference-based machine learning methods that show promising results in drug-target prediction, these methods possess inevitable limitations, where: 1) results are often biased as it lacks negative samples in the classification-based methods, and 2) novel drug-target associations with new (or isolated) drugs/targets cannot be explored by inference-based methods. As big data continues to boom, there is a need to study a scalable, robust, and accurate solution that can process large heterogeneous datasets and yield valuable predictions.

Results

We introduce a drug-target prediction method that improved our previously proposed method from the three aspects: 1) we constructed a heterogeneous network which incorporates 12 repositories and includes 7 types of biomedical entities (#20,119 entities, # 194,296 associations), 2) we enhanced the feature learning method with Node2Vec, a scalable state-of-art feature learning method, 3) we integrate the originally proposed inference-based model with a classification model, which is further fine-tuned by a negative sample selection algorithm. The proposed method shows a better result for drug–target association prediction: 95.3% AUC ROC score compared to the existing methods in the 10-fold cross-validation tests. We studied the biased learning/testing in the network-based pairwise prediction, and conclude a best training strategy. Finally, we conducted a disease specific prediction task based on 20 diseases. New drug-target associations were successfully predicted with AUC ROC in average, 97.2% (validated based on the DrugBank 5.1.0). The experiments showed the reliability of the proposed method in predicting novel drug-target associations for the disease treatment.
Spatiotemporal dynamics of calcium transients during embryogenesis of Drosophila melanogaster
Authors: Markova Olga , Senatore Sébastien , Lenne Pierre-François
Published: February 2019

Calcium signaling plays a crucial role in the physiology of the organs but also in various aspects of the organogenesis of the embryo. High versatility of calcium signaling is encoded by the dynamic variation of intracellular calcium concentration. While the dynamics of calcium is important, little is known about it throughout the embryogenesis of the largest class of animals, insects. Here, we visualize calcium dynamics throughout embryogenesis of Drosophila using a fluorescent protein-based calcium indicator, GCaMP3, and report calcium transients in epithelium and neuronal tissues. Local calcium transients of varying duration were detected in the outer epithelium, trachea and neural cells. In addition, gap-junction-dependent calcium waves were identified at stage 16 in the outer epithelium and in the trachea at stage 17. Calcium transient waveform analysis revealed different characteristics as a function of the duration, location and frequency. Detailed characterization of calcium transients during embryogenesis of Drosophila will help us better understand the role of calcium signaling in embryogenesis and organogenesis of insects.
Hallucinations both in and out of context: An Active Inference Account
Authors: Benrimoh David , Parr Thomas , Adams Rick A. , Friston Karl
Published: February 2019

Hallucinations, including auditory verbal hallucinations (AVH), occur in both the healthy population and in psychotic conditions such as schizophrenia (often developing after a prodromal period). In addition, hallucinations can be in-context (they can be consistent with the environment, such as when one hallucinates the end of a sentence that has been repeated many times), or out-of-context (such as the bizarre hallucinations associated with schizophrenia). In previous work, we introduced a model of hallucinations as false (positive) inferences based on a (Markov decision process) formulation of active inference. In this work, we extend this model to include content – to disclose the computational mechanisms behind in- and out-of-context hallucinations. In active inference, sensory information is used to disambiguate alternative hypotheses about the causes of sensations. Sensory information is balanced against prior beliefs, and when this balance is tipped in the favor of prior beliefs, hallucinations can occur. We show that in-context hallucinations arise when (simulated) subjects cannot use sensory information to correct prior beliefs about hearing a voice, but beliefs about content (i.e. the sequential order of a sentence) remain accurate. When hallucinating subjects also have inaccurate beliefs about state transitions, out-of-context hallucinations occur; i.e. their hallucinated speech content is disordered. Furthermore, subjects with inaccurate beliefs about state transitions but an intact ability to use sensory information do not hallucinate and are reminiscent of prodromal patients. This work demonstrates the different computational mechanisms that may underlie the spectrum of hallucinatory experience – from the healthy population to psychotic states.
Concomitant chemotherapy increases radiotherapy-mediated DNA-damage in peripheral blood lymphocytes
Authors: Lorat Yvonne , Fleckenstein Jochen , Görlinger Patric , Rübe Christian , Rübe Claudia E.
Published: February 2019

53BP1-foci detection in peripheral blood lymphocytes (PBLs) by immunofluorescence microscopy (IFM) is a sensitive and quantifiable DNA-double-strand-break (DSB) marker. In addition, high-resolution transmission-electron-microscopy (TEM) with immunogold-labeling of 53BP1 and DSB-bound phosphorylated Ku70 (pKu70) can be used to determine the progression of the DNA-repair process. Here, we analyzed whether different modes of irradiation influence the formation of DSBs in the PBLs of patients with cancer, and whether accompanying chemotherapy influences the DSB-appearance.

We obtained 86 blood samples before and 0.1, 0.5 and 24 h after irradiation from patients with head and neck, or rectal cancers receiving radiotherapy (RT) or radio-chemotherapy (RCT). 53BP1-foci were quantified by IFM. In addition, TEM was used to quantify gold-labelled pKu70-dimers and 53BP1-clusters within euchromatin and heterochromatin of PBLs. During radiotherapy, persisting 53BP1-foci accumulated in PBLs with increasing numbers of administered RT-fractions. This 53BP1-foci accumulation was not influenced by irradiation technique applied (3D-conformal radiotherapy versus intensity-modulated radiotherapy), dose intensity per fraction, number of irradiation fields, or isodose volume. However, more 53BP1-foci were detected in PBLs of patients treated with accompanying chemotherapy. TEM analyses showed that DSBs, indicated by pKu70, were present for longer periods in PBLs of RCT-patients than in PBLs of RT-only-patients. Moreover, not every residual 53BP1-focus was equivalent to a remaining DSB, since pKu70 was not present at every damage site. Persistent 53BP1-clusters, visualized by TEM, without colocalizing pKu70 likely indicate chromatin alterations after repair completion, or possibly, defective repair. Therefore, IFM-53BP1-foci analyses alone are not adequate to determine individual repair capacity after irradiation of PBLs, as a DSB may be indicated by a 53BP1-focus but not every 53BP1-focus represents a DSB.

The level of DNA-damage during RT is influenced by the presence of accompanying chemotherapy.
A study on the influence of factors associated with organizational readiness for change in healthcare organizations using TISM
Authors: Vaishnavi V. , Suresh M. , Dutta Pankaj
Published: February 2019

Purpose

The purpose of this paper is to identify, analyze and develop a model to measure the interactions among different factors of organizational readiness for change in service sector specific to healthcare organization. The total interpretive structural modeling (TISM)-based readiness for change is to build a theoretical framework to understand the mutual interactions among the factors and to identify the driving and dependence power of these factors.

Design/methodology/approach

TISM is used to identify factors that contribute to analyze the readiness state before starting a change implementation process in healthcare. Matrice d’Impacts croises-multiplication applique´ a classement analysis is used to find the driving and dependent factors of change in healthcare.

Findings

This paper identified 12 factors of readiness for change from literature review followed by expert interview to understand the inner connection of factors and study inner relationships. The result says that state of affairs, recent trends in healthcare sector, technology advancement and interdependence among departments are key factors for readiness of change.

Research limitations/implications

This research mainly focused on readiness factors for change in the healthcare sector.

Practical implications

This study will be useful for researcher and practitioners to understand the readiness factors for change.

Originality/value

In this research work, TISM-based readiness for the change framework structural model has been proposed for healthcare organizations which is a new effort in the area of organizational change management in this sector.
When elephants fight: South African washing powder wars
Authors: Chipp Kerry , Maphalala Jabu
Published: February 2019

Learning outcomes

An understanding of the competitive landscape and consumer dynamics of an emerging market, especially how a small local company learns to take on and deal with global players. Similarly, embeddedness within a market leads to increasing the competitiveness of local brands as they understand local consumers better than international ones. Local brands are also more likely to use home-based and innovative marketing strategies.

Case overview/synopsis

Bliss Chemicals, through their flagship brand, MAQ washing powder, captured market share from global multinationals during a price war. Nevertheless, their competitive landscape and their customer base are dynamic; the company cannot afford to rest on its laurels for long. The case provides insight into the marketing activities of both large and medium enterprises in an emerging market. It also demonstrates the type of marketing activation that engenders strong consumers’ response.

Complexity academic level

The case can be used in undergraduate, MBA and executive education courses on marketing, consumer behaviour, bottom of the pyramid or international marketing courses. It could also be used in business strategy courses on market entry, dealing with stronger competitors, price wars and doing business in Africa.

Supplementary materials

Teaching Notes are available for educators only. Please contact your library to gain login details or email support@emeraldinsight.com to request teaching notes.

Subject code

CSS 8: Marketing
From baby boomer to millennials: the changing flavor of entrepreneurial traits
Authors: Pillai Deepa , Dam Leena B.
Published: February 2019

Learning outcomes

The learning outcomes are as follows: decision-making in the areas of business plan, business strategy, financial management, profit planning and marketing, learning from outer business environment, succession planning for first-generation entrepreneur and choosing appropriate source of financing and drivers for diversification.

Case overview/synopsis

Immersed in sipping green tea in his capacious office lounge, the octogenarian Arjun Mehta introspected on the trials and tribulations of his journey as an entrepreneur, the voyage which started four decades ago. From 1976 to 2018, the business has now traversed three generations. Starting with Spice Mart (Sole Proprietor) to Hindware and Lament Construction (partnership firms) to Starlite Homes Pvt. Ltd. (corporate entity), Mr Mehta witnessed transformation and restructuring in organization with every new generation which characterized the evolution of family business. Handholding children to take up the reins of Spice Mart was not a calculated choice. Yet it is remarkable to study the growth in organizational structure of the regional family business. As a self-made entrepreneur, morals, ethics and value system are vital ingredients steering the organic growth story. Third-generation Mehta’s are enterprising, aspiring and visionary. With the incorporation of a corporate entity, they convinced themselves to bring inorganic growth in their business. Arjun Mehta gleamed with pride as Spice Mart partakes an organized structure which had lost prominence with the second-generation entrepreneurs. But he is equally hammered with juxtaposed thoughts. He contemplates whether the integration of retail business with real estate corroborates sustainable innovation. Will independent businesses create the brand’s footprints perpetually? Should the millennial confine business natively or should they grow internationally and become a conglomerate?

Complexity academic level

The case can be exclusively taught to masters and executive education class of students pursuing entrepreneurship and business management courses. The case will supplement understanding of theories of entrepreneurship and dimensions of family businesses in emerging economies.

Supplementary materials

Teaching Notes are available for educators only. Please contact your library to gain login details or email support@emeraldinsight.com to request teaching notes.

Subject code

CSS 3: Entrepreneurship.
Developer constraints on housing supply in urban Ghana
Authors: Owusu-Ansah Anthony , Soyeh Kenneth W. , Asabere Paul K.
Published: February 2019

Purpose

This study aims to document the major underlying forces prohibiting housing development in urban Ghana. Previous studies in Ghana have not empirically examined these constraints, but an empirical examination of these factors would help to formulate proper policies to address the housing shortage problems in Ghana. This paper fills this gap.

Design/methodology/approach

Using a purposive sampling technique, the authors surveyed the chief executive officers (CEOs) of private real estate development companies within Accra and Tema with a Likert scale questionnaire to measure the severity of the factors hindering housing development in these areas.

Findings

The results show that real estate developers consider the supply problems in housing to be driven mainly by formal and informal institutional factors. A large percentage of the CEOs reported that land tenure arrangements, lengthy procedure involved in securing building permits and process of land acquisition and registration in Ghana were the major factors that significantly affected housing supply. The difficulty in accessing development funds, underdeveloped mortgage market and high interest rates were some of the market-based factors constraining housing development.

Originality/value

This study empirically examines the factors that hinder housing development in Ghana, making a clear distinction between the market and institutional forces. The paper proposes policy recommendations for a more effective and direct government intervention to improve urban housing supply.
Teleworkers in Italy: who are they? Do they make more?
Authors: Pigini Claudia , Staffolani Stefano
Published: February 2019

Purpose

The purpose of this paper is to investigate the determinants of the probability of being a teleworker and the extent of earnings differentials between teleworkers and traditional employees.

Design/methodology/approach

The analysis is grounded on a theoretical framework depicting endogenous telework assignment and wage variations based on individual bargaining. The empirical strategy allows for non-random telework assignment, generating from individual- and job-specific observed as well as unobserved factors.

Findings

Results are based on the Italian labor force survey and uncover a key role of gender, higher education and family composition as determinants of the probability of teleworking. Furthermore, teleworkers enjoy a wage premium ranging between 2.7 and 8 percent.

Originality/value

Accounting for observed individual and job-specific effects, by both standard linear regression and propensity score matching, largely reduces the extent of wage premium emerging from unconditional descriptives; the results of an endogenous switching regression model however suggest that failing to properly care for unobserved factors leads to the underestimation of returns to telework.
Statistical analysis of failure data for estimating reliability, availability and maintainability of an automated croissant production line
Authors: Tsarouhas Panagiotis
Published: February 2019

Purpose

The purpose of this paper is to compute reliability, availability and maintainability (RAM) indices to measure and improve the performance of an automated croissant production line under real working conditions. Based on this study, the authors demonstrate how RAM analysis is very useful for deciding maintenance intervals and for planning and organizing the adequate maintenance strategy.

Design/methodology/approach

The present work is carried out by analyzing failure and repair data based on statistical techniques. Descriptive statistics of the failure and repair data at workstation and line level were carried out. Trend and serial correlation tests validated the assumption of independence and identical distribution of the failure data were conducted. Moreover, the reliability and maintainability of both the croissant production line and its workstations have been estimated at different mission times with their best fit distribution.

Findings

The main objectives of the applied method are to understand the nature of the failure patterns, and to estimate the reliability and maintainability characteristics of the croissant production system in precise quantitative terms. The analysis identifies the critical points of the production line that require further improvement through effective maintenance strategy.

Originality/value

This study is anticipated to serve as an illuminating effort in conducting a complete RAM analysis and its effect on the performance of the system that works under real conditions. The advantage of the methodology is the continuous monitoring of the production process through appropriate indices, the utilization of which leads to a continuous cycle of improvement.
Peripheral blood eosinophilia is associated with the presence of skin ulcers in patients with systemic sclerosis
Authors: Hara Tomoyuki , Ikeda Takaharu , Inaba Yutaka , Kunimoto Kayo , Mikita Naoya , Kaminaka Chikako , Kanazawa Nobuo , Yamamoto Yuki , Tabata Kayoko , Fujii Takao , Jinnin Masatoshi
Published: February 2019

The role of eosinophil in systemic sclerosis (SSc) is still controversial. In the present study, the relationship between skin ulcers and peripheral blood eosinophilia were analyzed in patients with SSc. We retrospectively investigated the clinical records of all patients who were diagnosed with SSc on the basis of American College of Rheumatology/European League Against Rheumatism 2013 criteria, and were followed up for more than 2 years at Wakayama Medical University. As a result, maximum eosinophil counts during the 2‐year follow‐up period were 20–983/mm3 (median, 270), whereas maximum eosinophil percentages were 0.5–14.1% (median, 5.3%) in peripheral blood of 47 SSc patients. On the other hand, patients with skin ulcers during the 2‐year follow up showed significantly increased maximum eosinophil counts compared with those without (median, 520 vs 228/mm3; P = 0.0001). Maximum eosinophil percentage was also significantly higher in patients with skin ulcers (median, 9.7% vs 4.6%; P = 0.00001). To note, in four of the nine patients with skin ulcers, the timing of emerging of the maximum eosinophil counts was associated with the ulcer development during the 2‐year follow up. These results suggest that eosinophils are involved in the pathogenesis of vascular dysfunction of SSc. Larger studies should be performed to clarify the exact mechanism of ulcer formation caused by eosinophilia in SSc patients in the future.
Energy of acoustic signals in a borehole
Authors: Markova I. , Ronquillo Jarillo G. , Markov M.
Published: February 2019

In the present article, the dependencies of the acoustic signal total energy and the energies of the wave packets of different types of the waves on the elastic parameters and permeability of rocks have been studied. We have considered traditional logging tools containing acoustical monopole source. Calculations were performed in a frequency range of dozens of kilohertz, typical for acoustic well logging. It was shown that in a typical high‐velocity formation (vs > vf, where vs and vf are the velocities of the shear wave in the rock and of the compressional wave in the borehole fluid, respectively), the pseudo‐Rayleigh waves, whose elastic properties depend mainly on the shear modulus of the rock, contributed significant energy to the total signal energy in the borehole. The energies of different wave packets depend on the permeability in different ways. The greatest sensitivity to permeability change has been shown by the acoustic signal total energy and the energy of the low‐velocity part of the pseudo‐Rayleigh wave packet. The theoretical analysis was illustrated by real sonic log data.
Dantrolene sodium increases calcium binding by human recombinant cardiac calsequestrin and calcium loading by sheep cardiac sarcoplasmic reticulum
Authors: Loescher Christine Margaret , Gibson Lynne Michelle , Stephenson Dimitrie George
Published: February 2019

Aim

Dantrolene interacts with ryanodine receptors in skeletal and cardiac muscle affecting sarcoplasmic reticulum calcium release. Since dantrolene is lipophilic it could also affect intra‐sarcoplasmic reticulum calcium handling proteins such as calsequestrin. This study investigated whether dantrolene (1‐30 µmol/L) alters the polymerization state and the calcium binding capacity of recombinant cardiac calsequestrin and cardiac sarcoplasmic reticulum calcium handling.

Methods

Human recombinant cardiac calsequestrin was used to make simultaneous measurements of turbidity (to indicate calsequestrin polymerization) and calcium binding to calsequestrin in the presence and absence of dantrolene. Caffeine‐induced Ca2+ transients were used to investigate the effects of dantrolene on sarcoplasmic reticulum calcium loading and release in saponin‐permeabilized cardiomyocytes laid down in monolayers in 96‐well array plates.

Results

Dantrolene (1‐30 µmol/L) increased the polymerization state of calsequestrin and its calcium binding capacity. In the presence of dantrolene, calsequestrin‐dependent turbidity increased 2.5‐11.5‐fold at 1.0 mmol/L calcium added to unbuffered Ca2+ solutions and 3‐10‐fold when calcium was raised from 0.06 to 30 µmol/L. The dantrolene‐dependent increase in turbidity at 30 µmol/L dantrolene was associated with a 3‐fold increase in the number of calcium ions bound per calsequestrin molecule at 30 and 100 µmol/L calcium. The caffeine‐induced releasable calcium loaded by the sarcoplasmic reticulum at 0.63 µmol/L free calcium in permeabilized cardiomyocytes was also increased in the presence of 30 µmol/L dantrolene.

Conclusion

Dantrolene alters the polymerization state and the calcium binding properties of cardiac calsequestrin and increases sarcoplasmic reticulum calcium loading in permeabilized cardiomyocytes.
Similar burden of type 2 diabetes among adult patients with sickle cell disease relative to African Americans in the U.S. population: a six‐year population‐based cohort analysis
Authors: Zhou Jifang , Han Jin , Nutescu Edith A. , Galanter William L. , Walton Surrey M. , Gordeuk Victor R. , Saraf Santosh L. , Calip Gregory S.
Published: February 2019

Conflicting evidence exists on the epidemiology of type 2 diabetes mellitus (T2DM) among patients with sickle cell disease (SCD). This study measured the prevalence, incidence and clinical outcomes associated with T2DM in a large US population of commercially‐insured adults aged ≥20 years with SCD between 2009 and 2014. Among 7070 patients with SCD, the mean age (median) was 39 (37) years and 60·8% were female. The standardized prevalence of T2DM among patients with SCD showed a modest increase, from 15·7% to 16·5% (P trend = 0·026), and was comparable to African‐American respondents to the National Health and Nutrition Examination Survey (18·2%). Over 17 024 person‐years, the crude incidence rate for T2DM was 25·4 per 1000 person‐years. Incident T2DM was associated with comorbid hypertension (hazard ratio [HR] = 1·45, 95% confidence interval [CI] 1·14–1·83), and dyslipidaemia (HR = 1·43, 95%CI 1·04–1·96). Compared to SCD patients without T2DM, more SCD patients with T2DM had diagnoses of nephropathy (28·0% vs. 9·5%; P < 0·001), neuropathy (17·7% vs. 5·2%; P < 0·001) and stroke (24·1% vs. 9·2%; P < 0·001). Prevalence of T2DM in SCD patients is similar to the general African American population with an increasing trend in recent years. These trends support routine screening for T2DM in aging patients with SCD, especially those with comorbid hypertension and/or dyslipidaemia.
Targeting amyloid clearance in Alzheimer's disease as a therapeutic strategy
Authors: Nalivaeva Natalia N. , Turner Anthony J.
Published: February 2019

Targeting the amyloid‐β (Aβ) peptide cascade has been at the heart of therapeutic developments in Alzheimer's disease (AD) research for more than 25 years, yet no successful drugs have reached the marketplace based on this hypothesis. Nevertheless, the genetic and other evidence remains strong, if not overwhelming, that Aβ is central to the disease process. Most attention has focused on the biosynthesis of Aβ from its precursor protein through the successive actions of the β‐ and γ‐secretases leading to the development of inhibitors of these membrane proteases. However, the levels of Aβ are maintained through a balance of its biosynthesis and clearance, which occurs both through further proteolysis by a family of amyloid‐degrading enzymes (ADEs) and by a variety of transport processes. The development of late‐onset AD appears to arise from a failure of these clearance mechanisms rather than by overproduction of the peptide. This review focuses on the nature of these clearance mechanisms, particularly the various proteases known to be involved, and their regulation and potential as therapeutic targets in AD drug development. The majority of the ADEs are zinc metalloproteases [e.g., the neprilysin (NEP) family, insulin‐degrading enzyme, and angiotensin converting enzymes (ACE)]. Strategies for up‐regulating the expression and activity of these enzymes, such as genetic, epigenetic, stem cell technology, and other pharmacological approaches, will be highlighted. Modifiable physiological mechanisms affecting the efficiency of Aβ clearance, including brain perfusion, obesity, diabetes, and sleep, will also be outlined. These new insights provide optimism for future therapeutic developments in AD research.

Linked Articles

This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc