bluuebunny/crossref_metadata_2025 huggingface dataset:
Speaker-normalized vowel representations in the human auditory cortex
Authors: Sjerps Matthias J. , Fox Neal P. , Johnson Keith , Chang Edward F.
Published: August 2018

Humans identify speech sounds, the fundamental building blocks of spoken language, using the same cues, or acoustic dimensions, as those that differentiate the voices of different speakers. The correct interpretation of speech cues is hence uncertain, and requires normalizing to the specific speaker. Here we assess how the human brain uses speaker-related contextual information to constrain the processing of speech cues. Using high-density electrocorticography, we recorded local neural activity from the cortical surface of participants who were engaged in a speech sound identification task. The speech sounds were preceded by speech from different speakers whose voices differed along the same acoustic dimension that differentiated the target speech sounds (the first formant; the lowest resonance frequency of the vocal tract). We found that the same acoustic speech sound tokens were perceived differently, and evoked different neural responses in auditory cortex, when they were heard in the context of different speakers. Such normalization involved the rescaling of acoustic-phonetic representations of speech, demonstrating a form of recoding before the signal is mapped onto phonemes or higher level linguistic units. This process is the result of auditory cortex’ sensitivity to the contrast between the dominant frequencies in speech sounds and those in their just preceding context. These findings provide important insights into the mechanistic implementation of normalization in human listeners. Moreover, they provide the first direct evidence of speaker-normalized speech sound representations in human parabelt auditory cortex, highlighting its critical role in resolving variability in sensory signals.
A large scale systemic RNAi screen in the red flour beetleTribolium castaneumidentifies novel genes involved in insect muscle development
Authors: Schultheis Dorothea , Weißkopf Matthias , Schaub Christoph , Ansari Salim , Dao Van Anh , Grossmann Daniela , Majumdar Upalparna , Hakeemi Muhammad Salim , Troelenberg Nicole , Richter Tobias , Schmitt-Engel Christian , Schwirz Jonas , Ströhlein Nadi , Teuscher Matthias , Bucher Gregor , Frasch Manfred
Published: August 2018

Although muscle development has been widely studied inDrosophila melanogasterthere are still many gaps in our knowledge, and it is not known to which extent this knowledge can be transferred to other insects. To help in closing these gaps we participated in a large-scale RNAi screen that used the red flour beetle,Tribolium castaneum, as a screening platform. The effects of systemic RNAi were screened upon double-stranded RNA injections into appropriate muscle-EGFP tester strains. Injections into pupae were followed by the analysis of the late embryonic/early larval muscle patterns, and injections into larvae by the analysis of the adult thoracic muscle patterns. Herein we describe the results of the first-pass screens with pupal and larval injections, which covered ~8,500 and ~5,000 genes, respectively, of a total of ~16,500 genes of theTriboliumgenome. Apart from many genes known fromDrosophilaas regulators of muscle development, a collection of genes previously unconnected to muscle development yielded phenotypes in larval body wall and leg muscles as well as in indirect flight muscles. We then present the main candidates from the pupal injection screen that remained after being processed through a series of verification and selection steps. Further, we discuss why distinct though overlapping sets of genes are revealed by theDrosophilaandTriboliumscreening approaches.
Positive human health effects of sea spray aerosols: molecular evidence from exposed lung cell lines
Authors: Asselman Jana , Acker Emmanuel Van , Rijcke Maarten De , Tilleman Laurentijn , Nieuwerburgh Filip Van , Mees Jan , De Schamphelaere Karel A.C. , Janssen Colin R.
Published: August 2018

Sea spray aerosols (SSAs) have profound effects on climate and ecosystems. Furthermore, the presence of microbiota and biogenic molecules, produced by among others marine phytoplankton, in SSAs could lead to potential human health effects. Yet the exposure and effects of SSAs on human health remain poorly studied. Here, we exposed human epithelial lung cells to different concentrations of extracts of a natural sea spray aerosol (SSA), a laboratory-generated SSA, the marine algal toxin homoyessotoxin and a chemical mTOR inhibitor. The mTOR inhibitor was included as it has been hypothesized that natural SSAs may influence the mTOR cell signaling pathway. We observed significant effects on the mTOR pathway and PCSK9 in all exposures. Based on these expression patterns, a clear dose response relationship was observed. Our results indicate a potential for positive health effects when lung cells are exposed to environmentally relevant concentrations of natural SSAs, whereas potential negative effects were observed at high levels of the laboratory SSA and the marine algal toxin. Overall, these results provide a substantial molecular evidence base for potential positive health effects of SSAs at environmentally relevant concentrations through the mTOR pathway. The results provided here suggest that SSAs contain biomolecules with significant pharmaceutical potential in targeting PCSK9.
A Multiplexed DNA FISH strategy for Assessing Genome Architecture inC. elegans
Authors: Fields Brandon , Nguyen Son C. , Nir Guy , Kennedy Scott
Published: August 2018

Eukaryotic DNA is highly organized within nuclei and this genomic organization is important for genome function. Fluorescentin situhybridization (FISH) approaches allow the 3D architecture of genomes to be visualized. Scalable FISH technologies, which can be applied to whole animals, are needed to help unravel how genomic architecture regulates, or is regulated by, development, growth, reproduction, and aging. Here, we describe a multiplexed DNA FISH Oligopaint library that targets the entireC. elegansgenome at chromosome, three megabase, and 500 kb scales. We describe a hybridization strategy that provides flexibility to DNA FISH experiments by coupling a single primary probe synthesis reaction to dye conjugated detection oligos via bridge oligos, eliminating the time and cost typically associated with labeling probe sets for individual DNA FISH experiments. The approach allows visualization of genome organization at varying scales in all/most cells across all stages of development in an intact animal model system.
A divergent kinase lacking the glycine-rich loop regulates membrane ultrastructure of theToxoplasmaparasitophorous vacuole
Authors: Beraki Tsebaot , Xiaoyu Hu , Broncel Malgorzata , Young Joanna C. , O’Shaughnessy William J. , Borek Dominika M. , Treeck Moritz , Reese Michael L.
Published: August 2018

Apicomplexan parasites replicate within a protective organelle called the parasitophorous vacuole (PV). TheToxoplasma gondiiPV is filled with a network of tubulated membranes, which are thought to facilitate trafficking of effectors and nutrients. Despite being critical to parasite virulence, there is scant mechanistic understanding of the network’s functions. Here, we identify the parasite secreted kinase WNG1 as a critical regulator of tubular membrane biogenesis. WNG1 family members adopt an atypical protein kinase fold lacking the glycine rich ATP-binding loop that is required for catalysis in canonical kinases. Unexpectedly, we find that WNG1 is an active protein kinase that localizes to the PV lumen and phosphorylates PV-resident proteins, several of which are essential for the formation of a functional intravacuolar network. Moreover, we show that WNG1-dependent phosphorylation of these proteins is required for their membrane association, and thus their ability to tubulate membranes. Consequently, WNG1 knockout parasites have an aberrant PV membrane ultrastructure. Collectively, our results describe a unique family ofToxoplasmakinases and implicate phosphorylation of secreted proteins as a mechanism of regulating PV formation during parasite infection.
Revealing evolutionary constraints on proteins through sequence analysis
Authors: Wang Shou-Wen , Bitbol Anne-Florence , Wingreen Ned S.
Published: August 2018

Statistical analysis of alignments of large numbers of protein sequences has revealed “sectors” of collectively coevolving amino acids in several protein families. Here, we show that selection acting on any functional property of a protein, represented by an additive trait, can give rise to such a sector. As an illustration of a selected trait, we consider the elastic energy of an important conformational change within an elastic network model, and we show that selection acting on this energy leads to correlations among residues. For this concrete example and more generally, we demonstrate that the main signature of functional sectors lies in the small-eigenvalue modes of the covariance matrix of the selected sequences. However, secondary signatures of these functional sectors also exist in the extensively-studied large-eigenvalue modes. Our simple, general model leads us to propose a principled method to identify functional sectors, along with the magnitudes of mutational effects, from sequence data. We further demonstrate the robustness of these functional sectors to various forms of selection, and the robustness of our approach to the identification of multiple selected traits.

Author summary

Proteins play crucial parts in all cellular processes, and their functions are encoded in their amino-acid sequences. Recently, statistical analyses of protein sequence alignments have demonstrated the existence of “sectors” of collectively correlated amino acids. What is the origin of these sectors? Here, we propose a simple underlying origin of protein sectors: they can arise from selection acting on any collective protein property. We find that the main signature of these functional sectors lies in the low-eigenvalue modes of the covariance matrix of the selected sequences. A better understanding of protein sectors will make it possible to discern collective protein properties directly from sequences, as well as to design new functional sequences, with far-reaching applications in synthetic biology.
Arnav: Site specific error models to identify variants in RNA
Authors: Ramu Avinash , Conrad Donald F.
Published: August 2018

We present Arnav (Analysis of RNA variants) a lightweight and easy-to-use statistical method for detecting mutations from RNA sequencing data. Site-specific error models allow Arnav to call variants with high specificity when the true variant allele fraction is unknown. We show the utility of Arnav by identifying variants using RNA sequencing data from the GTEx project.

Availability and Implementation

Arnav is implemented in C++ and is distributed under the GPL license at https://github.com/gatoravi/arnav.

Contact

aramu@wustl.edu
Optic Nerve Tortuosity and Globe Proptosis in Normal and Glaucoma Subjects
Authors: Wang Xiaofei , Rumpel Helmut , Baskaran Mani , Tun Tin A , Strouthidis Nicholas , Perera Shamira A , Nongpiur Monisha E , Hoe Lim Winston Eng , Aung Tin , Milea Dan , Girard Michaël J. A.
Published: August 2018

Purpose

To assess the difference in optic nerve tortuosity during eye movements and globe proptosis between primary open angle glaucoma and normal subjects using orbital magnetic resonance imaging.

Methods

10 Chinese subjects matched for age, ethnicity and refractive errors were recruited, including five normal controls and five patients with primary open angle glaucoma. All subjects underwent magnetic resonance imaging to assess their optic nerves and globes for three eye positions: primary gaze, adduction and abduction. Optic nerve tortuosity (optic nerve length divided by the distance between two ends) and globe proptosis (maximum distance between cornea and interzygomatic line) were measured from magnetic resonance imaging images.

Results

In adduction, the tortuosity of normal eyes was significantly larger than that of the glaucomatous eyes. Optic nerve tortuosity in adduction in the control and glaucoma groups were 1.004±0.003 (mean ± standard deviation) and 1.001±0.001, respectively (p=0.037). Globe proptosis (primary gaze) in glaucoma subjects (19.14±2.11 mm) was significantly higher than that in control subjects (15.32±2.79 mm; p = 0.046).

Conclusions

In this sample, subjects with glaucoma exhibited more taut optic nerves and more protruding eye globes compared to normal eyes. This may impact optic nerve head deformations in anatomically predisposed patients.

Précis

Eyes with glaucoma have tauter optic nerves compared with normal eyes, which may exert more force on the optic nerve head tissues during eye movements.
FACT and Ubp10 collaborate to modulate H2B deubiquitination and nucleosome dynamics
Authors: Nune Melesse , Morgan Michael , Connell Zaily , McCullough Laura , Jbara Muhammad , Sun Hao , Brik Ashraf , Formosa Tim , Wolberger Cynthia
Published: August 2018

Monoubiquitination of histone H2B (H2B-Ub) plays a role in transcription and DNA replication, and is required for normal localization of the histone chaperone, FACT. In yeast, H2B-Ub is deubiquitinated by Ubp8, a subunit of SAGA, and Ubp10. Although they target the same substrate, loss of Ubp8 and Ubp10 causes different phenotypes and alters the transcription of different genes. We show that Ubp10 has poor activity on yeast nucleosomes, but that addition of FACT stimulates Ubp10 activity on nucleosomes and not on other substrates. Consistent with a role for FACT in deubiquitinating H2Bin vivo, a FACT mutant strain shows elevated levels of H2B-Ub. Combination of FACT mutants with deletion of Ubp10, but not Ubp8, confers increased sensitivity to hydroxyurea and activates a cryptic transcription reporter, suggesting that FACT and Ubp10 may coordinate nucleosome assembly during DNA replication and transcription. Our findings reveal unexpected interplay between H2B deubiquitination and nucleosome dynamics.
Early Life Trauma Predicts Affective Phenomenology and the Effects are Partly Mediated by Staging Coupled with Lowered Lipid-Associated Antioxidant Defences
Authors: Maes Michael , Congio Ana , Moraes Juliana Brum , Bonifacio Kamila Landucci , Barbosa Decio Sabbatini , Vargas Heber Odebrecht , Morris Gerwyn , Puri Basant K. , Michelin Ana Paula , Vargas Nunes Sandra Odebrecht
Published: August 2018

Background

Early life trauma (ELT) may drive mood disorder phenomenology, neuro-oxidative and neuro-immune pathways and impairments in semantic memory. Nevertheless, there are no data regarding the impact of ELT on affective phenomenology and whether these pathways are mediated by staging or lowered lipid-associated antioxidant defences.

Methods

This study examined healthy controls (n=54) and patients with affective disorders including major depression, bipolar disorder and anxiety disorders (n=118). ELT was assessed using the Child Trauma Questionnaire. In addition, we measured affective phenomenology and assayed advanced oxidation protein products; malondialdehyde, paraoxonase 1 (CMPAase) activity, high-sensitivity C-reactive protein (hsCRP), and high-density lipoprotein (HDL) cholesterol.

Results

ELT was associated with increased risk for mood and comorbid anxiety disorders and a more severe phenomenology, including staging characteristics (number of mood episodes), severity of depression and anxiety, suicide attempts, suicidal ideation, type of treatments received, disabilities, body mass index, smoking behaviour and hsCRP, as well as lowered health-related quality of life, socio-economic status, antioxidant defences and semantic memory. The number of mood episodes and CMPAase/HDL-cholesterol levels could be reliably combined into a new vulnerability staging-biomarker index, which mediates in part the effects of ELT on affective phenomenology, while lowered antioxidant defences are associated with increased oxidative stress. Moreover, the effects of female sex on mood disorders and affective phenomenology are mediated by ELT.

Discussion

The cumulative effects of different types of ELT drive many aspects of affective phenomenology either directly or indirectly through effects of staging and/or lipid–associated antioxidant defences. The results show that children, especially girls, with ELT are at great risk to develop mood disorders and more severe phenotypes of affective disorders.
Learning 2-in-1: Towards Integrated EEG-fMRI-Neurofeedback
Authors: Perronnet Lorraine , Lécuyer Anatole , Mano Marsel , Fleury Mathis , Lioi Giulia , Cury Claire , Clerc Maureen , Lotte Fabien , Barillot Christian
Published: August 2018

Neurofeedback (NF) allows to exert self-regulation over specific aspects of one’s own brain activity by returning information extracted in real-time from brain activity measures. These measures are usually acquired from a single modality, most commonly electroencephalography (EEG) or functional magnetic resonance imaging (fMRI). EEG-fMRI-neurofeedback (EEG-fMRI-NF) is a new approach that consists in providing a NF based simultaneously on EEG and fMRI signals. By exploiting the complementarity of these two modalities, EEG-fMRI-NF opens a new spectrum of possibilities for defining bimodal NF targets that could be more robust, flexible and effective than unimodal ones. Since EEG-fMRI-NF allows for a richer amount of information to be fed back, the question arises of how to represent the EEG and fMRI features simultaneously in order to allow the subject to achieve better self-regulation. In this work, we propose to represent EEG and fMRI features in a single bimodal feedback (integrated feedback). We introduce two integrated feedback strategies for EEG-fMRI-NF and compare their early effects on a motor imagery task with a between-group design. The BiDim group (n=10) was shown a two-dimensional (2D) feedback in which each dimension depicted the information from one modality. The UniDim group (n=10) was shown a one-dimensional (1D) feedback that integrated both types of information even further by merging them into one. Online fMRI activations were significantly higher in the UniDim group than in the BiDim group, which suggests that the 1D feedback is easier to control than the 2D feedback. However subjects from the BiDim group produced more specific BOLD activations with a notably stronger activation in the right superior parietal lobe (BiDim > UniDim, p < 0.001, uncorrected). These results suggest that the 2D feedback encourages subjects to explore their strategies to recruit more specific brain patterns. To summarize, our study shows that 1D and 2D integrated feedbacks are effective but also appear to be complementary and could therefore be used in a bimodal NF training program. Altogether, our study paves the way to novel integrated feedback strategies for the development of flexible and effective bimodal NF paradigms that fully exploits bimodal information and are adapted to clinical applications.
A 3-fold kernel approach for characterizing Late Onset Alzheimer’s Disease
Authors: Squillario Margherita , Tomasi Federico , Tozzo Veronica , Barla Annalisa , Uberti Daniela ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: August 2018

The purpose of this study is to identify a global and robust signature characterizing Alzheimer’s Disease (AD). Two public GWAS datasets were analyzed considering a 3-fold kernel approach, based on SNPs, Genes and Pathways analysis, and two binary classifications tasks were addressed: cases@controls and APOE4 task. In the SNP signature of the ADNI-1 and ADNI-2 datasets, chromosome 19 and 20 reached high classification accuracy. In addition, the functional characterization of ADNI-1 and ADNI-2 SNP signatures found enriched the same pathway (i.e., Neuroactive ligand-receptor interaction), with GRM7 gene in common with both. TOMM40 was confirmed linked to AD pathology by SNP, gene and pathway-based analyses in ADNI-1. Using this 3-fold kernel approach, a peculiar signature of SNPs, genes and pathways has been highlighted in both datasets. Based on these significant results, we retain such approach a valuable tool to elucidate the heritable susceptibility to AD but also to other similar complex diseases.
Mining ancient microbiomes using selective enrichment of damaged DNA molecules
Authors: Weiß Clemens L. , Gansauge Marie-Theres , Aximu-Petri Ayinuer , Meyer Matthias , Burbano Hernán A.
Published: August 2018

Background

The identification of bona fide microbial taxa in microbiomes derived from ancient and historical samples is complicated by the unavoidable mixture between DNA from ante- and post-mortem microbial colonizers. One possibility to distinguish between these sources of microbial DNA is querying for the presence of age-associated degradation patterns typical of ancient DNA (aDNA). The presence of uracils, resulting from cytosine deamination, has been detected ubiquitously in aDNA retrieved from diverse sources, and used as an authentication criterion. Here, we employ a library preparation method that separates molecules that carry uracils from those that do not for a set of samples that includes Neandertal remains, herbarium specimens and archaeological plant remains.

Results

We show that sequencing DNA libraries enriched in molecules carrying uracils effectively amplifies age associated degradation patterns in microbial mixtures of ancient and historical origin. This facilitates the discovery of authentic ancient microbial taxa in cases where degradation patterns are difficult to detect due to large sequence divergence in microbial mixtures. Additionally, the relative enrichment of taxa in the uracil enriched fraction can help to identify bona fide ancient microbial taxa that could be missed using a more targeted approach.

Conclusions

Our experiments show, that in addition to its use in enriching authentic endogenous DNA of organisms of interest, the selective enrichment of damaged DNA molecules can be a valuable tool in the discovery of ancient microbial taxa.
Reward revaluation biases hippocampal replay content away from the preferred outcome
Authors: Carey Alyssa A. , Tanaka Youki , van der Meer Matthijs A. A.
Published: August 2018

The rodent hippocampus spontaneously generates bursts of neural activity (“replay”) which can depict spatial trajectories to reward locations, suggesting a role in model-based behavioral control. A largely separate literature emphasizes reward revaluation as the litmus test for such control, yet the content of hippocampal replay under revaluation conditions is unknown. We report that the content of awake hippocampal sharp wave-ripple events is biased away from the preferred outcome following reward revaluation, challenging the idea that such sequences reflect recent experience or trajectories toward the preferred goal.
Allele-specific genome editing using CRISPR-Cas9 causes off-target mutations in diploid yeast
Authors: Gorter de Vries Arthur R. , Couwenberg Lucas G. F. , van den Broek Marcel , de la Torre Cortés Pilar , Horst Jolanda ter , Pronk Jack T. , Daran Jean-Marc G.
Published: August 2018

Targeted DNA double-strand breaks (DSBs) with CRISPR-Cas9 have revolutionized genetic modification by enabling efficient genome editing in a broad range of eukaryotic systems. Accurate gene editing is possible with near-perfect efficiency in haploid or (predominantly) homozygous genomes. However, genomes exhibiting polyploidy and/or high degrees of heterozygosity are less amenable to genetic modification. Here, we report an up to 99-fold lower gene editing efficiency when editing individual heterozygous loci in the yeast genome. Moreover, Cas9-mediated introduction of a DSB resulted in large scale loss of heterozygosity affecting DNA regions up to 360 kb that resulted in introduction of nearly 1700 off-target mutations, due to replacement of sequences on the targeted chromosome by corresponding sequences from its non-targeted homolog. The observed patterns of loss of heterozygosity were consistent with homology directed repair. The extent and frequency of loss of heterozygosity represent a novel mutagenic side-effect of Cas9-mediated genome editing, which would have to be taken into account in eukaryotic gene editing. In addition to contributing to the limited genetic amenability of heterozygous yeasts, Cas9-mediated loss of heterozygosity could be particularly deleterious for human gene therapy, as loss of heterozygous functional copies of anti-proliferative and pro-apoptotic genes is a known path to cancer.
Transcription activity contributes to the firing of non-constitutive origins in Trypanosoma brucei
Authors: da Silva Marcelo S. , Cayres-Silva Gustavo R. , Vitarelli Marcela O. , Marin Paula A. , Hiraiwa Priscila M. , Araújo Christiane B. , Ávila Andrea R. , Reis Marcelo S. , Elias Maria Carolina
Published: August 2018

The cosynthesis of DNA and RNA potentially generates conflicts between replication and transcription, which can lead to genomic instability. In trypanosomatids, eukaryotic parasites that perform polycistronic transcription, this phenomenon and its consequences have not yet been investigated. Here, using equations and computational analysis we demonstrated that the number of constitutive origins mapped in the Trypanosoma brucei genome is close to the minimum required to complete replication within S phase duration. However, taking into account the location of these origins in the genome, the replication in due time becomes virtually impossible, making it necessary to activate non-constitutive origins. Moreover, computational and biological assays pointed to transcription being responsible for activating non-constitutive origins. Together, our results suggest that transcription action through conflicts with replication contributes to the firing of non-constitutive origins, maintaining the robustness of S phase duration. The usage of this entire pool of origins seems to be of paramount importance for the survival of this parasite that infects million people around the world since it contributes to the maintenance of the replication of its DNA.
Fitness Landscape of the Fission Yeast Genome
Authors: Grech Leanne , Jeffares Daniel Charlton , Sadée Christoph Yves , Rodríguez-López María , Bitton Danny Asher , Hoti Mimoza , Biagosch Carolina , Aravani Dimitra , Speekenbrink Maarten , Illingworth Christopher J. R. , Schiffer Philipp H. , Pidoux Alison L. , Tong Pin , Tallada Victor A. , Allshire Robin , Levin Henry L. , Bähler Jürg
Published: August 2018

Background

Non-protein-coding regions of eukaryotic genomes remain poorly understood. Diversity studies, comparative genomics and biochemical outputs of genomic sites can be indicators of functional elements, but none produce fine-scale genome-wide descriptions of all functional elements.

Results

Towards the generation of a comprehensive description of functional elements in the haploid Schizosaccharomyces pombe genome, we generated transposon mutagenesis libraries to a density of one insertion per 13 nucleotides of the genome. We applied a five-state hidden Markov model (HMM) to characterise insertion-depleted regions at nucleotide-level resolution. HMM-defined functional constraint was consistent with genetic diversity, comparative genomics, gene-expression data and genome annotation.

Conclusions

We infer that transposon insertions lead to fitness consequences in 90% of the genome, including 80% of the non-protein-coding regions, reflecting the presence of numerous non-coding elements in this compact genome that have functional roles. Display of this data in genome browsers provides fine-scale views of structure-function relationships within specific genes.
High-order epistasis in catalytic power of dihydrofolate reductase gives rise to a rugged fitness landscape in the presence of trimethoprim selection
Authors: Tamer Yusuf Talha , Gaszek Ilona K. , Abdizadeh Haleh , Batur Tugce Altinusak , Reynolds Kimberly , Atilgan Ali Rana , Atilgan Canan , Toprak Erdal
Published: August 2018

Evolutionary fitness landscapes of certain antibiotic target enzymes have been comprehensively mapped showing strong high order epistasis between mutations, but understanding these effects at the biochemical and molecular levels remained open. Here, we carried out an extensive experimental and computational study to quantitatively understand the evolutionary dynamics of Escherichia coli dihydrofolate reductase (DHFR) enzyme in the presence of trimethoprim induced selection. Biochemical and structural characterization of resistance-conferring mutations targeting a total of ten residues spanning the substrate binding pocket of DHFR revealed distinct resistance mechanisms. Next, we experimentally measured biochemical parameters (Km, Ki, and kcat) for a mutant library carrying all possible combinations of six resistance-conferring DHFR mutations and quantified epistatic interactions between them. We found that the epistasis between DHFR mutations is high-order for catalytic power of DHFR (kcat and Km), but less prevalent for trimethoprim affinity (Ki). Taken together our data provide a concrete illustration of how epistatic coupling at the level of biochemical parameters can give rise to complex fitness landscapes, and suggest new strategies for developing mutant specific inhibitors.
Gut microbial features can predict host phenotype response to protein deficiency
Authors: Navarro Guadalupe , Sharma Anukriti , Dugas Lara R. , Forrester Terrence , Gilbert Jack A. , Layden Brian T.
Published: August 2018

Malnutrition remains a major health problem in low and middle income countries. During low protein intake, < 0.67 g/kg/day, there is a loss of nitrogen (N2) balance, due to the unavailability of amino acid for metabolism and unbalanced protein catabolism results. However, there are individuals, who consume the same low protein intake, and preserve N2 balance for unknown reasons. A novel factor, the gut microbiota, may account for these N2 balance differences. To investigate this, we correlated gut microbial profiles with the growth of four murine strains (C57Bl6/J, CD-1, FVB, and NIH-Swiss) on protein deficient (PD) diet. Results show that a PD diet exerts a strain-dependent impact on growth and N2 balance as determined through analysis of urinary urea, ammonia and creatinine excretion. Bacterial alpha diversity was significantly (p < 0.05, FDR) lower across all strains on a PD diet compared to normal chow (NC). Multi-group analyses of the composition of microbiomes (ANCOM) revealed significantly differential microbial signatures between the four strains independent of diet. However, mice on a PD diet demonstrated differential enrichment of bacterial genera including, Allobaculum (C57Bl6/J), Parabacteroides (CD-1), Turicibacter (FVB), and Mucispirillum (NIH-Swiss) relative to NC. Additionally, statistical model fitting revealed that the relative abundance of genera such as Bifidobacterium, Ruminococcus, and Lactobacillus were significantly positively correlated with body weight, while Anaerofustis, Roseburia, and Bilophila were significantly positively correlated with ammonia excretion. Taken together, these results suggest a potential relationship between the specific gut microbiota, N2 balance and animal response to malnutrition.
Development of an experimental set-up for low-temperature spectroscopic studies of matrix-isolated molecules and molecular ices using synchrotron radiation
Authors: Singh Param Jeet , Sundararajan K. , Shastri Aparna , Kumar Vijay , Das Asim Kumar , Kush P. K. , Raja Sekhar B. N.
Published: August 2018

An experimental set-up for studying photophysics and photochemistry of molecules in an inert gas medium (matrix-isolated) and in the ice phase at low temperatures has been developed and commissioned at the Photophysics beamline, Indus-1 synchrotron radiation source. This end-station uses an in-house-developed closed-cycle cryostat for achieving cryo-temperatures (∼10 K). Synchrotron radiation from the Photophysics beamline is used as the source of UV–VUV photons and the system is equipped with a Fourier transform infrared spectrometer for characterization of the molecular species formed at low temperature. Various individual components of the end-station like closed-cycle cryostat, experimental chamber, gas mixing and deposition systems are tested to ascertain that the desired performance criteria are satisfied. The performance of the composite system after integration with the Photophysics beamline is evaluated by recording IR and UV–VUV photoabsorption spectra of sulfur dioxide at low temperatures (10 K), both in the ice phase as well as isolated in argon matrices. Results obtained are in good agreement with earlier literature, thus validating the satisfactory performance of the system. As an off-shoot of the study, the VUV absorption spectrum of matrix-isolated SO2 in argon matrix up to 10.2 eV is reported here for the first time. This experimental end-station will provide new opportunities to study photon-induced reactions in molecules of environmental, astrochemical and industrial importance. Details of the design, development and initial experimental results obtained are presented.
Accountants’ proactivity in intra-organisational networks: a strong structuration perspective
Authors: Daff Lyn , Jack Lisa
Published: August 2018

Purpose

The purpose of this paper is to provide insights into the importance of accountants’ networks inside organisations, the parties who comprise those networks and how accountants go about building and maintaining their networks. It also illustrates the use of strong structuration theory, which specifically considers the networks that surround agents. The theoretical discussion highlights the significance of communication as agency in the context of accounting practice through a strong structuration perspective.

Design/methodology/approach

A qualitative approach to the inquiry was adopted. Interviews were conducted with 30 Australian accountants from 22 not-for-profit organisations. A thematic approach was used to analyse the transcripts. Structuration theory, supplemented by strong structuration, informed the study.

Findings

The interviewees attested to the importance of communication and developing networks within their organisations. They actively sought to expand and enhance their networks. The accountants played a pivotal role in networks and they pursued both horizontal and vertical relations. The accountants’ knowledge of organisational positions and perceptions of their own roles were used strategically in attempts to alter the internal structures of networked others.

Research limitations/implications

The interviewed accountants worked in not-for-profit organisations and this may influence the findings. Future research might consider accountants working in for-profit organisations. The study provides insights into strategies to develop intra-organisational networks.

Originality/value

The study contributes to the meagre literature regarding accountants’ networks within organisations. It provides insights that may assist accountants in enhancing their own networks. Although structuration theory is well-established in accounting research, the enrichments offered by strong structuration are illustrated in this study.
Are we ready?
Authors: Shrivastava Archana , Naik Asha
Published: August 2018

Subject area

Human Resource Management and Business Strategy.

Study level/applicability

Postgraduate.

Case overview

The case provides a holistic perspective of organizational transformation, management of change impact on employees and leader behavior. The challenge at Govind Milk and Milk Products Pvt. Ltd. a mid-size company, in the dairy industry was to transform itself into a pan India and global company from a regional organization. The case study outlines how the organization took on the transformation journey under a strong leadership and managed change by focusing on creating a brand, implementing technology and creating a culture of meritocracy. Having made the successful transition from being a family run business to a professionally managed company and having built significant internal capacity the big question is – Can the company strive and thrive in the VUCA business environment?

Expected learning outcomes

To highlight the process and management of organizational change. To highlight the role of leadership in the process of organizational change. To understand how the environmental factors or the VUCA environment impacts the performance of an organization. To highlight internal capacity building as a strategy to deal with the VUCA environment.

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: 6: Human Resource Management.
Wonder Pedicabs: leisure rickshaw rides
Authors: Jain Vranda , Srivastava Vinita
Published: August 2018

Subject area

Marketing Management and Economics.

Study level/applicability

Management courses (MBA level), Courses on Tourism

Case overview

When in India (WII) is a tour company serving the niche segment of Heritage tourism. WII was incorporated in 2011 with the aim to enable foreign and domestic tourists to experience the deeply embedded cultural ethos and heritage of Old Delhi. Their unique tourism product, “the Wonder Pedicabs”, provides leisure rickshaw rides through the Old Delhi lanes. This teaching case focuses on various managerial dimensions of the operations of WII. The case can be used in courses on Marketing as well as Economics. The case discusses the macro and micro environmental forces operating on WII. It deliberates on the economics of various tours offered by WII. It also educates the participants about the process of decision-making that goes into the selection of a tour operator and a tourism product. Hence, it appreciates the significance of need recognition, search for information, evaluation of alternatives and purchase decision as pillars in the process of decision-making process. The case also attempts to educate the participants about the Indian Tourism Sector.

Expected learning outcomes

Comprehend what constitutes a tourism product and types of tourism. Understand consumer decision-making for a tourism product. Highlight the importance of the tourism sector in the Indian economy. Discuss economic concepts pertaining to cost and volume, enabling managerial decision-making.

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 12: Tourism and Hospitality.
Amazon India’s “Apni Dukaan”: branding strategy
Authors: Yadav Neetu , Sagar Mahim
Published: August 2018

Subject area

Brand Management, Branding Strategy, Strategic Management.

Study level/applicability

The case study is suitable for postgraduate management programs, such as MBA, Executive MBA and executive development programs.

Case overview

This case study provides a detailed analysis of Amazon India’s branding strategy by way of analyzing popular branding campaigns such as “Try to kar”, “Aur Dikhao”, “Kya Pehnu” and “Apni Dukaan” that enabled the global brand to reach to the masses of Tier-II and Tier-III cities in India. Facing fierce competition from existing market leaders such as Flipkart and Snapdeal, Amazon India strategizes to attract Indian consumers by rightly capturing their behavior in terms of demanding “highest power of options”, “fashion choices”, “originality” and “trust” with its local flavored advertisement campaigns enabling it to create a “trusted, reliable and local” brand identity. With the help of sufficient data and numbers about the industry, company and competitors, the analysis presents a clear picture of the current status of Amazon in the Indian e-commerce space and leaves the readers with food for thought concerning whether this “culture-specific” branding strategy will enable Amazon to become the number one choice for Indian online shoppers in the near future.

Expected learning outcomes

This case study helps students to understand how global MNCs use unique branding strategies to capture mass-markets in e-commerce business, the role of culture-specific aspects in developing differentiation strategies and the role of local flavors in branding strategies and internationalization.

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.
Lean Six-Sigma: the means to healing an ailing NHS?
Authors: Bancroft John , Saha Krish , Li Di , Lukacs Gabor , Pierron Xavier
Published: August 2018

Purpose

The purpose of this paper is to examine England’s Accident and Emergency (A&E) arm of the National Health Service (NHS). It considers the positive impact that Lean has had and Six-Sigma can have in A&E departments to improve the quality and reliability of the service offered, in an area that is facing performance challenges.

Design/methodology/approach

Independent variables average monthly temperature data (degrees Celsius) obtained from the Met Office and weekly A&E data, patient volume is analysed alongside the dependent variable, the percentage of patients seen in 4 h or less.

Findings

The model produced a robust positive impact when Lean Six-Sigma is adopted, increasing the likelihood of A&E dependents meeting their performance objective to see and treat patients in 4 h or less.

Research limitations/implications

Further variables such as staffing levels, A&E admission type should be considered in future studies. Additionally, it would add further clarity to analyse hospitals and trusts individually, to gauge which are struggling.

Practical implications

Should the NHS further its understanding and adoption of Lean Six-Sigma, it is believed this could have significant improvements in productivity, patient care and cost reduction.

Social implications

Productivity improvements will allow the NHS to do more with an equal amount of funding, therefore improving capacity and patient care.

Originality/value

Through observing A&E and its ability to treat patients in a timely fashion it is clear the NHS is struggling to meet its performance objectives, the recommendation of Six-Sigma in A&E should improve the reliability and quality of care offered to patients.
Achieving better revenue and customers’ satisfaction with after-sales services
Authors: Borchardt Miriam , Souza Marcelo , Pereira Giancarlo M. , Viegas Claudia V.
Published: August 2018

Purpose

Branded car dealerships with best revenue by serviced car also have the best after-sales customers’ satisfaction level. The purpose of this paper is to present the analysis of the after-sales quality management practices adopted by dealerships with the best performance in terms of customer’s satisfaction and revenue and how such practices contribute to these results.

Design/methodology/approach

A multiple case study was performed with nine leader branded car dealerships in an emerging country, considering the entrance car. The performance indicators to evaluate customers’ satisfaction, revenue and operational indicators related to product support, brand manifestation and relationship with customers were identified. Quality management practices that support the best results achievement were analyzed.

Findings

The three dealerships that represent Asiatic brands have best customers’ satisfaction and revenue performance. These dealerships typically have different processes comparing with dealerships that represent European and American brands concerning to: continuous improvement management; warranties and stock management; services scheduling; offer bonuses to customers; and customers service that emphasizes focus on technical and commercial expertise.

Originality/value

This research considered indicators performance and, based on that, analyzed the dealerships’ practices that support the best performance. Such aspect has room for academic literature since the quality management research related to car industry focuses mainly on manufacturer and generates managerial insights to the car industry and its dealerships.
Inspection tables for single acceptance sampling with crisp and fuzzy formulation of quality limits
Authors: Chukhrova Nataliya , Johannssen Arne
Published: August 2018

Purpose

The purpose of this paper is to construct innovative exact and approximative sampling plans for acceptance sampling in statistical quality control. These sampling plans are determined for crisp and fuzzy formulation of quality limits, various lot sizes and common α- and β-levels.

Design/methodology/approach

The authors use generalized fuzzy hypothesis testing to determine sampling plans with fuzzified quality limits. This test method allows a consideration of the indifference zone related to expert opinion or user priorities. In addition to the exact sampling plans calculated with the hypergeometric operating characteristic function, the authors consider approximative sampling plans using a little known, but excellent operating characteristic function. Further, a comprehensive sensitivity analysis of calculated sampling plans is performed, in order to examine how the inspection effort depends on crisp and fuzzy formulation of quality limits, the lot size and specifications of the producer’s and consumer’s risks.

Findings

The results related the parametric sensitivity analysis of the calculated sampling plans and the conclusions regarding the approximation quality provide the user a comprehensive basis for a direct implementation of the sampling plans in practice.

Originality/value

The constructed sampling plans ensure the simultaneous control of producer’s and consumer’s risks with the smallest possible inspection effort on the one hand and a consideration of expert opinion or user priorities on the other hand.
Constrained optimal design of X̅ control chart with multiple assignable causes under Burr XII failure mechanism
Authors: Saadatmeli Aitin , Bameni Moghadam Mohamad , Seif Asghar , Faraz Alireza
Published: August 2018

Purpose

The purpose of this paper is to develop a cost model by the variable sampling interval and optimization of the average cost per unit of time. The paper considers an economic–statistical design of the X̅ control charts under the Burr shock model and multiple assignable causes were considered and compared with three types of prior distribution for the mean shift parameter.

Design/methodology/approach

The design of the modified X̅ chart is based on the two new concepts of adjusted average time to signal and average number of false alarms for X̅ control chart under Burr XII shock model with multiple assignable causes.

Findings

The cost model was examined through a numerical example, with the same cost and time parameters, so the optimal of design parameters were obtained under uniform and non-uniform sampling schemes. Furthermore, a sensitivity analysis was conducted in a way that the variability of loss cost and design parameters was evaluated supporting the changes of cost, time and Burr XII distribution parameters.

Research limitations/implications

The economic–statistical model scheme of X̅ chart was developed for the Burr XII distributed with multiple assignable causes. The correlated data are among the assumptions to be examined. Moreover, the optimal schemes for the economic-statistic chart can be expanded for correlated observation and continuous process.

Practical implications

The economic–statistical design of control charts depends on the process shock model distribution and due to difficulties from both theoretical and practical aspects; one of the proper alternatives may be the Burr XII distribution which is quite flexible. Yet, in Burr distribution context, only one assignable cause model was considered where more realistic approach may be to consider multiple assignable causes.

Originality/value

This study presents an advanced theoretical model for cost model that improved the shock model that presented in the literature. The study obviously indicates important evidence to justify the implementation of cost models in a real-life industry.