bluuebunny/crossref_metadata_2025 huggingface dataset:
Antibiotic-induced cell chaining triggers pneumococcal competence by reshaping quorum sensing to autocrine signaling
Authors: Domenech Arnau , Slager Jelle , Veening Jan-Willem
Published: March 2018

Streptococcus pneumoniaecan acquire antibiotic resistance by activation of competence and subsequent DNA uptake. Several antibiotics induce competence by disrupting protein-quality control or perturbing DNA replication. Here, we demonstrate that aztreonam (AZT) and clavulanic acid (CLA) also promote competence. We show that both compounds induce cell chain formation by targeting the D,D-carboxypeptidase PBP3. In support of the hypothesis that chain formation promotes competence, we demonstrate that an autolysin mutant (lytB) is hypercompetent. As competence is initiated by the binding of a small extracellular peptide (CSP) to a membrane-anchored receptor (ComD), we wondered if chain formation alters CSP diffusion and thereby sensing by ComD. Indeed, the presence of AZT or CLA affects competence synchronization by switching CSP-based quorum sensing to autocrine-like signaling, as CSP is retained to chained cells and no longer shared in a common pool. Together, these insights demonstrate the versatility of quorum sensing in integrating different stresses and highlight that certain antibiotics should be prescribed with care not to drive the spread of antibiotic resistance.
Refactoring the upper sugar metabolism ofPseudomonas putidafor co-utilization of disaccharides, pentoses, and hexoses
Authors: Dvořák Pavel , de Lorenzo Víctor
Published: March 2018

Given its capacity to tolerate stress, NAD(P)H/ NAD(P) balance, and increased ATP levels, the platform strainPseudomonas putidaEM42, a genome-edited derivative of the soil bacteriumP. putidaKT2440, can efficiently host a suite of harsh reactions of biotechnological interest. Because of the lifestyle of the original isolate, however, the nutritional repertoire ofP. putidaEM42 is centered largely on organic acids, aromatic compounds and some hexoses (glucose and fructose). To enlarge the biochemical network ofP. putidaEM42 to include disaccharides and pentoses, we implanted heterologous genetic modules for D-cellobiose and D-xylose metabolism into the enzymatic complement of this strain. Cellobiose was actively transported into the cells through the ABC complex formed by native proteins PP1015-PP1018. The knocked-in β-glucosidase BglC fromThermobifida fuscacatalyzed intracellular cleavage of the disaccharide to D-glucose, which was then channelled to the default central metabolism. Xylose oxidation to the dead end product D-xylonate was prevented by by deleting thegcdgene that encodes the broad substrate range quinone-dependent glucose dehydrogenase. Intracellular intake was then engineered by expressing theEscherichia coliproton-coupled symporter XylE. The sugar was further metabolized by the products ofE. coli xylA(xylose isomerase) andxylB(xylulokinase) towards the pentose phosphate pathway. The resultingP. putidastrain co-utilized xylose with glucose or cellobiose to complete depletion of the sugars. These results not only show the broadening of the metabolic capacity of a soil bacterium towards new substrates, but also promoteP. putidaEM42 as a platform for plug-in of new biochemical pathways for utilization and valorization of carbohydrate mixtures from lignocellulose processing.
Auxin-Mediated Sterility Induction System for Longevity and Mating Studies inCaenorhabditis elegans
Authors: Kasimatis Katja R. , Moerdyk-Schauecker Megan J. , Phillips Patrick C.
Published: March 2018

The ability to control both the means and timing of sexual reproduction provides a powerful tool to understand not only fertilization, but also life history trade-offs resulting from sexual reproduction. However, precisely controlling fertilization has proved a major challenge across model systems. An ideal sterility induction system should be external, non-toxic, and reversible. Using the auxin-inducible degradation system targeting thespe-44gene within the nematodeCaenorhabditis elegans, we designed a means of externally inducing spermatogenesis arrest. We show that exposure to auxin during larval development induces both hermaphrodite self-sterility and male sterility. Moreover, male sterility can be reversed upon cessation of auxin exposure. The sterility induction system developed here has multiple applications in the fields of spermatogenesis and mating systems evolution. Importantly, this system is also a highly applicable tool for aging studies. We show that auxin-induced self-sterility is comparable to the commonly used chemically-induced FUdR sterility, while offering multiple benefits, including being less labor intensive, being non-toxic, and avoiding compound interactions with other experimental treatments.
6mer Seed Toxicity Determines Strand Selection in miRNAs
Authors: Gao Quan Q. , Putzbach William E. , Murmann Andrea E. , Chen Siquan , Ambrosini Giovanna , Peter Johannes M. , Bartom Elizabeth T. , Peter Marcus E.
Published: March 2018

Many siRNAs and shRNAs are toxic to cancer cells through a 6mer seed sequence (position 2-7 of the guide strand). A siRNA screen with all 4096 possible 6mer seed sequences in a neutral RNA backbone revealed a preference for guanine in positions 1-3 and a GC content of >80% of the 6mer seed in the most toxic siRNAs. These 6mer seed containing siRNAs exert their toxicity by targeting survival genes which contain GC-rich 3’UTRs. The master tumor suppressor miRNA miR-34a was found to be toxic through such a G-rich 6mer seed suggesting that certain tumor suppressive miRNAs use a toxic 6mer seed to kill cancer cells. An analysis of all mature miRNAs suggests that most miRNAs evolved to avoid guanine at the 5′ end of the 6mer seed sequence of the predominantly expressed arm. In contrast, for many tumor suppressive miRNAs the predominant arm contains a G-rich toxic 6mer seed, presumably to eliminate cancer cells.
NRG1 is required for the function of the TIR-NLR immune receptors Roq1 and RPP1 in Nicotiana. benthamiana
Authors: Qi Tiancong , Schultink Alex , Pham Julie , Cho Myeong-Je , Staskawicz Brian J.
Published: March 2018

The plant immune system involves a large family of nucleotide-binding leucine-rich repeat (NLR) intracellular immune receptors. These immune receptors often function to directly or indirectly mediate the perception of specific pathogen effector proteins secreted into the cell. Activation of these immune receptors typically results in activation of the immune system and subsequent suppression of pathogen proliferation. Although many examples of NLR receptors are known, a mechanistic understanding of how receptor activation ultimately leads to an immune response is not well understood. A subset of the NLR proteins contain a TIR domain at their N terminus (TNL). One such TNL, the N gene, was previously shown to depend on a non-TIR NLR protein, N requirement gene 1 (NRG1) for immune function. We tested additional NLR proteins in Nicotiana benthamiana for dependency on NRG1. We found that two additional TIR-NLR proteins, Roq1 and RPP1, also require NRG1 but that two coiled-coil NLR proteins, Bs2 and Rps2, do not. This finding suggests that NRG1 may be a conserved component of TNL signaling pathways.
A probabilistic interpretation of PID controllers using active inference
Authors: Baltieri Manuel , Buckley Christopher L.
Published: March 2018

In the past few decades, probabilistic interpretations of brain functions have become widespread in cognitive science and neuroscience. The Bayesian brain hypothesis, predictive coding, the free energy principle and active inference are increasingly popular theories of cognitive functions that claim to unify understandings of life and cognition within general mathematical frameworks derived from information theory, statistical physics and machine learning. Furthermore, it has been argued that one such proposal, active inference, combines both information and control theory and has its roots in cybernetics studies of the brain. The connections between information and control theory have been discussed since the 1950’s by scientists like Shannon and Kalman and have recently risen to prominence in modern stochastic optimal control theory. How-ever, the implications of the confluence of these two theoretical frame-works for the biological sciences have been slow to emerge. Here we argue that if the active inference proposal is to be taken as a general process theory for biological systems, we need to consider how existing control theoretical approaches to biological systems relate to it. In this work we will focus on PID (Proportional-Integral-Derivative) controllers, one of the most common types of regulators employed in engineering and more recently used to explain behaviour in biological systems, e.g. chemotaxis in bacteria and amoebae or robust adaptation in biochemical networks. Using active inference, we derive a probabilistic interpretation of PID controllers, showing how they can fit a more general theory of life and cognition under the principle of (variational) free energy minimisation once we use only simple linear generative models.
BisPin and BFAST-Gap: Mapping Bisulfite-Treated Reads
Authors: Porter Jacob , Zhang Liqing
Published: March 2018

Background

BisPin is a new multiprocess bisulfite-treated short DNA read mapper written in Python 2.7. It performs alignments using BFAST, leveraging its multithreading functionality and thorough hash-based indexing strategy. BisPin is feature rich and supports directional, nondirectional, PBAT, and hairpin construction strategies. BisPin approaches read mapping by converting the Cs to Ts and the Gs to As in both the reads and the reference genome. BisPin uses fast rescoring to disambiguate ambiguously aligned reads for a superior amount of uniquely mapped reads compared to other mappers. The performance of BisPin was evaluated on both real and simulated data in comparison to other read mappers.

BFAST-Gap is a modified version of BFAST meant for Ion Torrent reads. It uses a parameterized logistic function to determine the weights of the gap open and extension penalties based on the homopolymer run length of the DNA read. This is because the Ion Torrent sequencing technology can overcall and undercall homopolymer runs. BisPin works with both BFAST-Gap and BFAST. BFAST-Gap is compatible with indexes built with BFAST. There are few mappers that specifically address Ion Torrent data. BFAST-Gap works with Illumina reads as well.

Results

BisPin with BFAST consistently had a higher amount of uniquely mapped reads compared to other mappers on real data using a variety of construction strategies. Using a hairpin validation strategy, BisPin was superior using the maximum score, and it mapped 73% of reads correctly.

BisPin with BFAST-Gap on Ion Torrent reads with a logistic gap open penalty function improved mapping accuracy with real and simulated data. On simulated bisulfite Ion Torrent data, the area under the curve was improved by approximately seven, and on one real data set, the uniquely mapped percent was improved by seven percent. BFAST-Gap performed better than TMAP on simulated regular Ion Torrent reads, and TMAP is designed for Ion Torrent reads. Other read mappers had worse performance.

Conclusions

BisPin and BFAST-Gap have consistently good accuracy with a variety of data. BisPin is feature-rich. This makes BisPin and BFAST-Gap useful additions to read mapping software.
Reference-based annotation of single cell transcriptomes identifies a profibrotic macrophage niche after tissue injury
Authors: Aran Dvir , Looney Agnieszka P. , Liu Leqian , Fong Valerie , Hsu Austin , Wolters Paul J. , Abate Adam , Butte Atul J. , Bhattacharya Mallar
Published: March 2018

Myeloid cells localize to peripheral tissues in a wide range of pathologic contexts. However, appreciation of distinct myeloid subtypes has been limited by the signal averaging inherent to bulk sequencing approaches. Here we applied single-cell RNA sequencing (scRNA-seq) to map cellular heterogeneity in lung fibrosis induced by bleomycin injury in mice. We first developed a computational framework that enables unbiased, granular cell-type annotation of scRNA-seq. This approach identified a macrophage subpopulation that was specific to injured lung and notable for high expression of Cx3cr1+ and MHCII genes. We found that these macrophages, which bear a gene expression profile consistent with monocytic origin, progressively acquire alveolar macrophage identity and localize to sites of fibroblast accumulation. Probing their functional role, in vitro studies showed a trophic effect of these cells on fibroblast activation, and ablation of Cx3cr1-expressing cells suppressed fibrosis in vivo. We also found by gene set analysis and immunofluorescence that markers of these macrophages were upregulated in samples from patients with lung fibrosis compared with healthy controls. Taken together, our results uncover a specific pathologic subgroup of macrophages with markers that could enable their therapeutic targeting for fibrosis.
Complement receptor 1 gene (CR1) intragenic duplication and risk of Alzheimer’s disease
Authors: Kucukkilic Ezgi , Brookes Keeley , Barber Imelda , Guetta-Baranes Tamar , Morgan Kevin , Hollox Edward J
Published: March 2018

Single nucleotide variants (SNVs) within and surrounding the complement receptor 1 (CR1) gene show some of the strongest genome-wide association signals with late-onset Alzheimer’s disease. Some studies have suggested that this association signal is due to a duplication allele (CR1-B) of a low copy repeat (LCR) within theCR1gene, which increases the number of complement C3b/C4b-binding sites in the mature receptor. In this study, we develop a triplex paralogue ratio test (PRT) assay forCR1LCR copy number allowing large numbers of samples to be typed with a limited amount of DNA. We also develop aCR1-B allele-specific PCR based on the junction generated by an historical non-allelic homologous recombination event betweenCR1LCRs. We use these methods to genotypeCR1and measureCR1-B allele frequency in both late-onset and early-onset cases and unaffected controls from the United Kingdom. Our data support an association of late-onset Alzheimer’s disease with theCR1-B allele, and confirm that this allele occurs most frequently on the risk haplotype defined by SNV alleles. Furthermore, regression models incorporatingCR1-B genotype provide a bitter fit to our data compared to incorporating the SNP-defined risk haplotype, supporting theCR1-B allele as the variant underlying the increased risk of late-onset Alzheimer’s disease.
Establishment of signaling interactions with cellular resolution for every cell cycle of embryogenesis
Authors: Chen Long , Ho Vincy Wing Sze , Wong Ming-Kin , Huang Xiaotai , Chan Lu-yan , Ng Hon Chun Kaoru , Ren Xiaoliang , Yan Hong , Zhao Zhongying
Published: March 2018

Intercellular signaling interaction plays a key role in breaking fate symmetry during animal development. Identification of the signaling interaction at cellular resolution is technically challenging, especially in a developing embryo. Here we develop a platform that allows automated inference and validation of signaling interaction for every cell cycle ofC. elegansembryogenesis. This is achieved by generation of a systems-level cell contact map that consists of 1,114 highly confident intercellular contacts by modeling analysis and is validated through cell membrane labeling coupled with cell lineage analysis. We apply the map to identify cell pairs between which a Notch signaling interaction takes place. By generating expression patterns for two ligands and two receptors of Notch signaling pathway with cellular resolution using automated expression profiling technique, we are able to refine existing and identify novel Notch interactions duringC. elegansembryogenesis. Targeted cell ablation followed by cell lineage analysis demonstrates the roles of signaling interactions over cell division in breaking fate symmetry. We finally develop a website that allows online access to the cell-cell contact map for mapping of other signaling interaction in the community. The platform can be adapted to establish cellular interaction from any other signaling pathways.
Semi-soft Clustering of Single Cell Data
Authors: Zhu Lingxue , Lei Jing , Devlin Bernie , Roeder Kathryn
Published: March 2018

Motivated by the dynamics of development, in which cells of recognizable types, or pure cell types, transition into other types over time, we propose a method of semi-soft clustering that can classify both pure and intermediate cell types from data on gene expression or protein abundance from individual cells. Called SOUP, for Semi-sOft clUstering with Pure cells, this novel algorithm reveals the clustering structure for both pure cells, which belong to one single cluster, as well as transitional cells with soft memberships. SOUP involves a two-step process: identify the set of pure cells and then estimate a membership matrix. To find pure cells, SOUP uses the special block structure the K cell types form in a similarity matrix, devised by pairwise comparison of the gene expression profiles of individual cells. Once pure cells are identified, they provide the key information from which the membership matrix can be computed. SOUP is applicable to general clustering problems as well, as long as the unrestrictive modeling assumptions hold. The performance of SOUP is documented via extensive simulation studies. Using SOUP to analyze two single cell data sets from brain shows it produce sensible and interpretable results.
Chromatin features constrain structural variation across evolutionary timescales
Authors: Fudenberg Geoff , Pollard Katherine S.
Published: March 2018

The potential impact of structural variants includes not only the duplication or deletion of coding sequences, but also the perturbation of non-coding DNA regulatory elements and structural chromatin features, including topological domains (TADs). Structural variants disrupting TAD boundaries have been implicated both in cancer and developmental disease; this likely occurs via ‘enhancer hijacking’, whereby removal of the TAD boundary exposes enhancers to new target transcription start sites (TSSs). With this functional role, we hypothesized that boundaries would display evidence for negative selection. Here we demonstrate that the chromatin landscape constrains structural variation both within healthy humans and across primate evolution. In contrast, in patients with developmental delay, variants occur remarkably uniformly across genomic features, suggesting a potentially broad role for enhancer hijacking in human disease.
An inactivating mutation in the histone deacetylase SIRT6 causes human perinatal lethality
Authors: Ferrer Christina M. , Alders Marielle , Postma Alex V. , Park Seonmi , Klein Mark A. , Cetinbas Murat , Pajkrt Eva , Glas Astrid , van Koningsbruggen Silvana , Christoffels Vincent M. , Mannens Marcel M.A.M. , Knegt Lia , Etchegaray Jean-Pierre , Sadreyev Ruslan I. , Denu John M. , Mostoslavsky Gustavo , van Maarle Merel C. , Mostoslavsky Raul
Published: March 2018

It has been well established that histone and DNA modifications are critical to maintaining the equilibrium between pluripotency and differentiation during early embryogenesis. Mutations in key regulators of DNA methylation have shown that the balance between gene regulation and function is critical during neural development in early years of life. However, there have been no identified cases linking epigenetic regulators to aberrant human development and fetal demise. Here, we demonstrate that a homozygous inactivating mutation in the histone deacetylase SIRT6 results in severe congenital anomalies and perinatal lethality in four affected fetuses. In vitro, the amino acid change at Asp63 to a histidine results in virtually complete loss of H3K9 deacetylase and demyristoylase functions. Functionally, SIRT6 D63H mouse embryonic stem cells (mESCs) fail to repress pluripotent gene expression, direct targets of SIRT6, and exhibit an even more severe phenotype than Sirt6-deficient ESCs when differentiated into embryoid bodies (EBs). When terminally differentiated toward cardiomyocyte lineage, D63H mutant mESCs maintain expression of pluripotent genes and fail to form functional cardiomyocyte foci. Last, human induced pluripotent stem cells (iPSCs) derived from D63H homozygous fetuses fail to differentiate into EBs, functional cardiomyocytes, and neural progenitor cells due to a failure to repress pluripotent genes. Altogether, our study described a germline mutation in SIRT6 as a cause for fetal demise, defining SIRT6 as a key factor in human development and identifying the first mutation in a chromatin factor behind a human syndrome of perinatal lethality.
Design and implementation of crawling algorithm to collect deep web information for web archiving
Authors: Oh Hyo-Jung , Won Dong-Hyun , Kim Chonghyuck , Park Sung-Hee , Kim Yong
Published: March 2018

Purpose

The purpose of this paper is to describe the development of an algorithm for realizing web crawlers that automatically collect dynamically generated webpages from the deep web.

Design/methodology/approach

This study proposes and develops an algorithm to collect web information as if the web crawler gathers static webpages by managing script commands as links. The proposed web crawler actually experiments with the algorithm by collecting deep webpages.

Findings

Among the findings of this study is that if the actual crawling process provides search results as script pages, the outcome only collects the first page. However, the proposed algorithm can collect deep webpages in this case.

Research limitations/implications

To use a script as a link, a human must first analyze the web document. This study uses the web browser object provided by Microsoft Visual Studio as a script launcher, so it cannot collect deep webpages if the web browser object cannot launch the script, or if the web document contains script errors.

Practical implications

The research results show deep webs are estimated to have 450 to 550 times more information than surface webpages, and it is difficult to collect web documents. However, this algorithm helps to enable deep web collection through script runs.

Originality/value

This study presents a new method to be utilized with script links instead of adopting previous keywords. The proposed algorithm is available as an ordinary URL. From the conducted experiment, analysis of scripts on individual websites is needed to employ them as links.
The safe tweet: social media use by Ontario fire services
Authors: Lauricella Sharon , Pankhurst Kristy-Lynn
Published: March 2018

Purpose

The purpose of this paper is to examine how fire services use social media to educate the public about safety and fire prevention.

Design/methodology/approach

Grounded theoretical methods were employed in a rigorous qualitative analysis of five significant fire services’ Twitter accounts in Ontario, Canada.

Findings

Seven main themes emerged from the data, with an overarching conclusion that tweets made by fire service organisations and professionals do not focus primarily on fire safety.

Research limitations/implications

This paper addresses a gap in the literature in terms of understanding how social media communicates information about all three lines of defence against fire, with a focus on the first two: public fire safety education, fire safety standards and enforcement and emergency response.

Practical implications

The authors suggest that fire services need to employ a more segmented approach to social media posts with an objective to engage and educate the public.

Originality/value

This paper is the first extensive qualitative analysis to consider the particulars of fire services’ social media presence.
The analysis of entry of Ethiopian enterprises into the export-markets and the associated factors
Authors: Lemessa Sisay Diriba , Watabaji Mulugeta Damie , Yismaw Molla Alemayehu
Published: March 2018

Purpose

Though many studies in the past dealt with the survival and growth of enterprises both in the local- and export-markets, less attention was given to the analysis of the duration of enterprises entry into the export-markets. The aim of this paper is, therefore, to analyze the duration of Ethiopian enterprises entry into the export-markets.

Design/methodology/approach

This paper used data collected from 848 enterprises through a cross-sectional survey method conducted by the World Bank in 2015. In order to estimate the average duration – the time that enterprises need to wait before entering into the export-markets and the associated factors – the authors used the mixture of non-parametric (Kaplan-Meier) and parametric (Weibull) models.

Findings

The non-parametric results show that enterprises are required to wait for an average of about eight years before entering into the export-markets after their establishment. In addition, foreign-owned enterprises were found to be faster in entering into the export-markets than their domestically owned counterparts. The parametric results revealed that enterprises’ product innovation, enterprises’ size and age, and custom and trade regulations are factors that curtail the durations of enterprises entry into the export-markets. On the other hand, enterprises’ operational costs, the size of enterprises’ locality, and enterprises’ location are factors that slow the durations of enterprises’ entry into the export-markets.

Originality/value

This study is the first to offer pioneering evidences on the duration (time in years) that Ethiopian enterprises need to wait before entering into the export-markets and the factors that affect the length of their waiting time.
Existential leadership coaching in a medical partnership
Authors: Spencer Eric David , Albertyn Ruth
Published: March 2018

Purpose

This paper aims to report on a case study conducted in a private medical partnership of more than 50 specialist physicians where the researcher applied a leadership coaching model grounded in existential philosophy. The paper asserts that existential leadership coaching can be a novel and effective means to address leadership development needs in the unique context of a professional partnership.

Design/methodology/approach

The qualitative phenomenological study used a bounded case study design using four purposively selected specialist physicians who were involved in four individual structured coaching sessions over an eight-week period. Data came in writing from participants in the form of reflective questions before and after the coaching, and note-taking on index cards during the coaching process. Data also came from the coach/researcher as a participant observer in the form of note-taking and a reflective journal.

Findings

Findings indicate that working with perceptions of leadership in existential coaching conversations can provide a mechanism for members of a partnership to find greater purpose, and choose how they can contribute better to leadership development in their collective. Findings indicate that the process of imaging the perceptions of fellow partners can unlock the identification of and choice for developmental actions and contributions to the collective.

Research limitations/implications

For the selected qualitative design, the researcher as the participant observer provided advantages such as insider access and depth of engagement. The study was limited to a small sample in a particular time and context. Findings are thus viewed in the light of this unique case.

Practical implications

Such a qualitative phenomenological case study provides glimpses into the lives of real-life leaders and offers the coaching, academic and medical fraternities an insider understanding of leadership development in the case of professional partnerships.

Originality/value

The paper points to a mechanism which may be a means to unlock potential and facilitate leadership development in the context of professional partnerships.
Does external auditing combat corruption? Evidence from private firms
Authors: Farooq Omar , Shehata Nermeen F.
Published: March 2018

Purpose

This paper aims to document whether firms with audited financial statements pay lower bribes to get contracts than firms without audited financial statements. In other words, this study assesses whether external auditing helps combat corruption.

Design/methodology/approach

The World Bank Enterprise Survey data covering the period between 2006 and 2014 is used. The total sample comprised more than 50,000 firms in 126 countries.

Findings

This paper finds that firms with audited financial statements pay significantly lower bribes compared to firms with unaudited financial statements. The results are robust across various estimation procedures, various proxies for bribery and various sub-samples. It is also found that the relationship between audited financial statements and bribery is more pronounced in environments where firms face higher pressure to engage in corrupt practices.

Practical implications

The results imply that auditing of financial statements can act as a disciplining device to curb bribery in environments that encourage corruption.

Originality/value

This paper is the first attempt, according to the authors’ knowledge, to examine the relationship between external auditing and corruption using firm-level data that cover 126 countries and is gathered over a 14-year period. Therefore, the results derived from this study are generalizable.
Design, qualification and Shariah governance of stock screening methodologies in selected Gulf Cooperation Council (GCC) countries in comparison with the United States
Authors: Kasi Umayal , Muhammad Junaina
Published: March 2018

Purpose

This paper aims to compare and analyse the aspects of Shariah screening methodologies within the selected Gulf Cooperation Council (GCC) countries as well as comparing the methodologies with the USA, and to examine how Shariah screening methodologies affect financing and investing activities of a firm.

Design/methodology/approach

Shariah screening methodologies within the selected GCC countries and between the GCC countries and the USA are compared on the basis of the data collected from secondary sources.

Findings

Design, qualification and Shariah governance set the Shariah screening methodologies within the GCC countries apart. Feasibility, duration, economic viability and funds required differentiate these Shariah screening methodologies between the GCC countries and the USA. Shariah screening methodologies implied in the USA is more stringent than in the GCC countries.

Research limitations/implications

The suggestions in this study include using a longer research timeline, examining many more number of countries’ Shariah screening methodologies and exploring other types of Shariah screening methodologies.

Practical implications

The possibility of generalising the implementation of strict and uniform Shariah screening methodologies across all the country-specific Shariah indices amongst Muslim nations, globally, is likely to benefit all the Muslim countries, by strengthening the understanding, interaction and economic co-operation amongst these countries.

Social implications

People’s needs can be tended to if Maqasid Al-Shariah (objectives of Shariah) is achieved through flexibility, dynamism and creativity within the social policy.

Originality/value

Aspects of Shariah screening methodologies are compared and contrasted within the selected GCC countries as well as between the GCC countries and the United States and the role of Shariah screening methodologies is examined in order to determine the extent of what is Shariah-Compliant and what is Non-Shariah Compliant for a firm.
The Importance of Physical Literacy for Physical Education and Recreation
Authors: Basoglu Umut Davut
Published: March 2018

As the basis of characteristics, qualifications, behaviors, awareness, knowledge and understanding of the development of healthy active living and physical recreation opportunities Physical Literacy (PL); has become a global concern in the fields of physical education and recreation since its first use as a term. Experts from different countries and disciplines underline the necessity of expanding the PL context. Despite this international recognition, neither the existence of a work on PL in nor a model of PL in physical education programs has yet to be seen in Turkish literature. The aim of this study is to introduce such an important concept to Turkish literature by a comprehensive literature review and to present the prominence of PL in terms of physical education, physical activity and sports fields. In addition, under the scope of this study, undergraduate and graduate programs in which physical educators are trained to shape both all students and athletes are examined and various proposals are made about how to place PL in these programs. By examining the graduate and postgraduate programs of faculties of sport and physical education and sport sciences in 98 universities in Turkey and NCTR, we come to a conclusion that between the 3.-6. semesters of graduate programs, the introduction of the PL course, training and modules will increase the awareness and competence of the PL. Moreover we expect that it would be beneficial to train these field specialists and bring them to my country through the opening of specific post-graduate training programs in the field of PL.
Oxygen vacancy-passivated ZnO thin film formed by atomic layer deposition using H2O2
Authors: Wang Yue , Kang Kyung-Mun , Kim Minjae , Park Hyung-Ho
Published: March 2018

Intrinsic defect oxygen vacancies, which can easily form in ZnO films and result in a compensation effect on p-type dopants, have long prevented the preparation of high-quality p-type ZnO; consequently, the application of ZnO in optoelectronic devices has been adversely affected. Therefore, in this investigation, the passivation of oxygen vacancies in undoped ZnO using H2O2 as an oxygen source is studied using atomic layer deposition (ALD). The ALD growth window ranged from 60 to 150 °C, and the use of H2O2 as an oxygen source, instead of H2O, changed the preferred growth orientation from coexisting a- and c-axes to only the c-axis, which indicated that H2O2 can provide an oxygen-rich environment for the growth of ZnO. Photoluminescence results indicated that oxygen vacancies in the ZnO film reduced significantly when H2O2 was used as the oxygen precursor instead of H2O for film preparation. Further, oxygen vacancies can be suppressed more efficiently using H2O2 when ZnO films were deposited at lower temperatures than at high temperatures. A decrease in the optical bandgap and an increase in the work function were observed when films were prepared using H2O2 due to a lowering of the Fermi level. Therefore, the use of H2O2 as an oxygen source is effective in providing an oxygen-rich environment and passivating oxygen vacancies in ZnO, which might be beneficial for the preparation of p-type ZnO films.
Cell Swelling Induced by the Antimalarial KAE609 (Cipargamin) and Other PfATP4-Associated Antimalarials
Authors: Dennis Adelaide S. M. , Lehane Adele M. , Ridgway Melanie C. , Holleran John P. , Kirk Kiaran
Published: March 2018

For an increasing number of antimalarial agents identified in high-throughput phenotypic screens, there is evidence that they target PfATP4, a putative Na
+
efflux transporter on the plasma membrane of the human malaria parasite
Plasmodium falciparum
. For several such “PfATP4-associated” compounds, it has been noted that their addition to parasitized erythrocytes results in cell swelling. Here we show that six structurally diverse PfATP4-associated compounds, including the clinical candidate KAE609 (cipargamin), induce swelling of both isolated blood-stage parasites and intact parasitized erythrocytes. The swelling of isolated parasites is dependent on the presence of Na
+
in the external environment and may be attributed to the osmotic consequences of Na
+
uptake. The swelling of the parasitized erythrocyte results in an increase in its osmotic fragility. Countering cell swelling by increasing the osmolarity of the extracellular medium reduces the antiplasmodial efficacy of PfATP4-associated compounds, consistent with cell swelling playing a role in the antimalarial activity of this class of compounds.
Outcome of E1224-Benznidazole Combination Treatment for Infection with a Multidrug-Resistant Trypanosoma cruzi Strain in Mice
Authors: Diniz Lívia de Figueiredo , Mazzeti Ana Lia , Caldas Ivo Santana , Ribeiro Isabela , Bahia Maria Terezinha
Published: March 2018

Combination therapy has been proposed as an alternative therapeutic approach for the treatment of Chagas disease. In this study, we evaluated the effect of treatment with benznidazole combined with E1224 (ravuconazole prodrug) in an experimental murine model of acute infection. The first set of experiments assessed the range of E1224 doses required to induce parasitological cure using
Trypanosoma cruzi
strains with different susceptibilities to benznidazole (Y and Colombian). All E1224 doses were effective in suppressing the parasitemia and preventing death; however, parasitological cure was observed only in mice infected with Y strain. Considering these results, we evaluated the effect of combined treatment against Colombian, a multidrug-resistant
T. cruzi
strain. After exclusion of antagonistic effects using
in vitro
assays, infected mice were treated with E1224 and benznidazole in monotherapy or in combination at day 4 or 10 postinoculation. All treatments were well tolerated and effective in suppressing parasitemia; however, parasitological and PCR assays indicated no cure among mice treated with monotherapies. Intriguingly, the outcome of combination therapy was dependent on treatment onset. Early treatment using optimal doses of E1224-benznidazole induced a 100% cure rate, but this association could not eliminate a well-established infection. The beneficial effect of combination therapy was evidenced by further reductions of the patent parasitemia period in the group receiving combined therapy compared with monotherapies. Our results demonstrated a positive interaction between E1224 and benznidazole against murine
T. cruzi
infection using a multidrug-resistant strain and highlighted the importance of a stringent experimental model in the evaluation of new therapies.
Population Pharmacokinetic Analyses for Rezafungin (CD101) Efficacy Using Phase 1 Data
Authors: Lakota Elizabeth A. , Ong Voon , Flanagan Shawn , Rubino Christopher M.
Published: March 2018

Rezafungin (CD101) is a novel echinocandin antifungal agent currently in clinical development for the treatment of candidemia and invasive candidiasis. Rezafungin has potent
in vitro
activity against
Candida albicans
and
Candida glabrata
, including azole- and echinocandin-resistant isolates. The objective of this analysis was to develop a population pharmacokinetic (PK) model to characterize the disposition of rezafungin in plasma following intravenous (i.v.) administration. Data from two phase 1 studies, a single-ascending-dose study and a multiple-ascending-dose study, were available. Candidate population PK models were fit to the pooled data using the Monte Carlo parametric expectation maximization algorithm in S-ADAPT. The data were best described using a linear four-compartment model with zero-order drug input via i.v. infusion and first-order elimination. In order to account for the relationships between the structural PK parameters and subject body weight, all parameters in the model were scaled to subject body weight using standard allometric coefficients (a power of 0.75 for the clearance terms and 1.0 for the volume terms). The final model fit the observed data with very little bias and excellent precision. The prediction-corrected visual predictive check demonstrated that the final model could accurately simulate both the central tendency and the variability of observed rezafungin plasma concentrations. Given this, the final rezafungin population PK model is expected to provide reliable simulated concentration-time profiles and can provide dose selection decision support for future clinical studies.
Clinical Assessment of a Nocardia PCR-Based Assay for Diagnosis of Nocardiosis
Authors: Rouzaud Claire , Rodriguez-Nava Véronica , Catherinot Emilie , Méchaï Frédéric , Bergeron Emmanuelle , Farfour Eric , Scemla Anne , Poirée Sylvain , Delavaud Christophe , Mathieu Daniel , Durupt Stéphane , Larosa Fabrice , Lengelé Jean-Philippe , Christophe Jean-Louis , Suarez Felipe , Lortholary Olivier , Lebeaux David
Published: March 2018

The diagnosis of nocardiosis, a severe opportunistic infection, is challenging. We assessed the specificity and sensitivity of a 16S rRNA
Nocardia
PCR-based assay performed on clinical samples. In this multicenter study (January 2014 to April 2015), patients who were admitted to three hospitals and had an underlying condition favoring nocardiosis, clinical and radiological signs consistent with nocardiosis, and a
Nocardia
PCR assay result for a clinical sample were included. Patients were classified as negative control (NC) (negative
Nocardia
culture results and proven alternative diagnosis or improvement at 6 months without anti-
Nocardia
treatment), positive control (PC) (positive
Nocardia
culture results), or probable nocardiosis (positive
Nocardia
PCR results, negative
Nocardia
culture results, and no alternative diagnosis). Sixty-eight patients were included; 47 were classified as NC, 8 as PC, and 13 as probable nocardiosis. PCR results were negative for 35/47 NC patients (74%). For the 12 NC patients with positive PCR results, the PCR assay had been performed with respiratory samples. These NC patients had chronic bronchopulmonary disease more frequently than did the NC patients with negative PCR results (8/12 patients [67%] versus 11/35 patients [31%];
P
= 0.044). PCR results were positive for 7/8 PC patients (88%). There were 13 cases of probable nocardiosis, diagnosed solely using the PCR results; 9 of those patients (69%) had lung involvement (consolidation or nodule).
Nocardia
PCR testing had a specificity of 74% and a sensitivity of 88% for the diagnosis of nocardiosis.
Nocardia
PCR testing may be helpful for the diagnosis of nocardiosis in immunocompromised patients but interpretation of PCR results from respiratory samples is difficult, because the PCR assay may also detect colonization.
Monitoring Shedding of Five Genotypes of RotaTeq Vaccine Viruses by Genotype-Specific Real-Time Reverse Transcription-PCR Assays
Authors: Higashimoto Yuki , Ihira Masaru , Miyazaki Yu , Kuboshiki Ayumi , Yoshinaga Sayaka , Hiramatsu Hiroyuki , Suzuki Ryota , Miyata Masafumi , Miura Hiroki , Komoto Satoshi , Yukitake Jun , Taniguchi Koki , Kawamura Yoshiki , Yoshikawa Tetsushi
Published: March 2018

RotaTeq (RV5) is a widely used live attenuated pentavalent rotavirus (RV) vaccine. Although fecal shedding of RV vaccine strains persists for long time periods, it is unclear how each vaccine strain replicates in intestinal tissue and is excreted in stool. To examine this issue, we established RV5 genotype-specific real-time reverse transcription-PCR (RT-PCR) assays. Five real-time RT-PCR assays were designed for the VP7 gene in genotypes G1, G2, G3, G4, and G6. All assays exhibited excellent linearity, and the detection limit was 1 infectious unit (IU)/reaction for G2, G4, and G6 and 10 IUs/reaction for G1 and G3. No cross-reactivity was observed among G genotypes. The inter- and intra-assay coefficients of variation were less than 3%. The assays were used to examine 129 stool samples collected from eight infants who received RV5. In cases 1 and 2, who received three rounds of vaccination, RV shedding decreased gradually with the number of vaccinations. G1 and G6 shedding appeared to be predominant in comparison to shedding of the other genotypes. Patterns of fecal shedding of the five genotypes of vaccine viruses differed between the eight vaccine recipients. RV5 genotype-specific real-time RT-PCR assays will be useful to study the molecular biology of RV5 replication in infants and experimental animals.
TgTKL1 Is a Unique Plant-Like Nuclear Kinase That Plays an Essential Role in Acute Toxoplasmosis
Authors: Varberg Joseph M. , Coppens Isabelle , Arrizabalaga Gustavo , Gaji Rajshekhar Y.
Published: March 2018

In the protozoan parasite
Toxoplasma gondii
, protein kinases have been shown to play key roles in regulating parasite motility, invasion, replication, egress, and survival within the host. The tyrosine kinase-like (TKL) family of proteins are an unexplored set of kinases in
Toxoplasma
. Of the eight annotated TKLs in the
Toxoplasma
genome, a recent genome-wide loss-of-function screen showed that six are important for tachyzoite fitness. By utilizing an endogenous tagging approach, we showed that these six
T. gondii
TKLs (TgTKLs) localize to various subcellular compartments, including the nucleus, the cytosol, the inner membrane complex, and the Golgi apparatus. To gain insight into the function of TKLs in
Toxoplasma
, we first characterized TgTKL1, which contains the plant-like enhanced disease resistance 1 (EDR1) domain and localizes to the nucleus. TgTKL1 knockout parasites displayed significant defects in progression through the lytic cycle; we show that the defects were due to specific impairment of host cell attachment. Transcriptomics analysis identified over 200 genes of diverse functions that were differentially expressed in TgTKL1 knockout parasites. Importantly, numerous genes implicated in host cell attachment and invasion were among those most significantly downregulated, resulting in defects in microneme secretion and processing. Significantly, all of the mice inoculated intraperitoneally with TgTKL1 knockout parasites survived the infection, suggesting that TgTKL1 plays an essential role in acute toxoplasmosis. Together, these findings suggest that TgTKL1 mediates a signaling pathway that regulates the expression of multiple factors required for parasite virulence, underscoring the potential of this kinase as a novel therapeutic target.

IMPORTANCE
Toxoplasma gondii
is a protozoan parasite that can cause chronic and life-threatening disease in mammals; new drugs are greatly needed for treatment. One attractive group of drug targets consists of parasite kinases containing unique features that distinguish them from host proteins. In this report, we identify and characterize a previously unstudied kinase, TgTKL1, that localizes to the nucleus and contains a domain architecture unique to plants and protozoa. By disrupting TgTKL1, we showed that this kinase is required for the proper expression of hundreds of genes, including many that are required for the parasite to gain entry into the host cell. Specifically, parasites lacking TgTKL1 have defects in host cell attachment, resulting in impaired growth
in vitro
and a complete loss of virulence in mice. This report provides insight into the importance of the parasite tyrosine kinase-like kinases and establishes TgTKL1 as a novel and essential virulence factor in
Toxoplasma
.