bluuebunny/crossref_metadata_2025 huggingface dataset:
A genetically encoded fluorescent sensor for in vivo imaging of GABA
Authors: Marvin Jonathan S. , Shimoda Yoshiteru , Malgoire Vincent , Leite Marco , Kawashima Takashi , Jensen Thomas P. , Knott Erika L. , Novak Ondrej , Podgorski Kaspar , Leidenheimer Nancy J. , Rusakov Dmitri A. , Ahrens Misha B. , Kullmann Dimitri M. , Looger Loren L.
Published: May 2018

Current techniques for monitoring GABA, the primary inhibitory neurotransmitter in vertebrates, cannot follow ephemeral transients in intact neural circuits. We applied the design principles used to create iGluSnFR, a fluorescent reporter of synaptic glutamate, to develop a GABA sensor using a protein derived from a previously unsequenced Pseudomonas fluorescens strain. Structure-guided mutagenesis and library screening led to a usable iGABASnFR (ΔF/Fmax ~ 2.5, Kd ~ 9 μM, good specificity, adequate kinetics). iGABASnFR is genetically encoded, detects single action potential-evoked GABA release events in culture, and produces readily detectable fluorescence increases in vivo in mice and zebrafish. iGABASnFR enabled tracking of: (1) mitochondrial GABA content and its modulation by an anticonvulsant; (2) swimming-evoked GABAergic transmission in zebrafish cerebellum; (3) GABA release events during inter-ictal spikes and seizures in awake mice; and (4) GABAergic tone decreases during isoflurane anesthesia. iGABASnFR will permit high spatiotemporal resolution of GABA signaling in intact preparations.
Measures of reproducibility in sampling and laboratory processing methods in high-throughput microbiome analysis
Authors: Vera-Wolf Patricia , Cárdenas Juan P. , Morton Amanda M. , Norambuena Tomás , Torres Rafael , Leon Luis E. , Bik Elisabeth M. , Ugalde Juan A. , Almonacid Daniel E. , Richman Jessica , Apte Zachary S
Published: May 2018

Microbial community analysis can be biased by multiple technical factors, such as storage conditions, DNA extraction, or amplification conditions. In a high-throughput laboratory that relies on samples obtained from thousands of different subjects, knowledge of the extent of subject-introduced sampling and storage variation on the outcome of the inferred microbiome, as well as the effect of laboratory-introduced variation caused by reagent batches, equipment, or operator on the consistency of these processes within the laboratory is paramount. Here, we analyzed the effect of sampling from different parts of the same stool specimen or on different consecutive days, as well as short-term storage of samples at different temperatures on microbiome profiles obtained by 16S rRNA gene amplification. Each of these factors had relatively little effect on the microbial composition. In addition, replicate amplification of 44 stool samples showed reproducible results. Finally, 363 independent replicate extractions and amplifications of a single human homogenized stool (HS) specimen showed reproducible results (average Lin’s correlation = 0.95), with little variation introduced by HS batch, operator, extraction equipment, or DNA sequencer. In all cases, variations between replicates were significantly smaller than those between individual samples; subject identity always was the largest determinant. We propose that homogenized stool specimens could be used as quality control to routinely monitor the laboratory process and to validate new methods.
Analysis of differentially methylated regions in primates and non-primates provides support for the evolutionary hypothesis of schizophrenia
Authors: Banerjee Niladri , Polushina Tatiana , Bettella Francesco , Steen Vidar M. , Andreassen Ole A. , Hellard Stephanie Le
Published: May 2018

Introduction

The persistence of schizophrenia in human populations separated by geography and time led to the evolutionary hypothesis that proposes schizophrenia as a by-product of the higher cognitive abilities of modern humans. To explore this hypothesis, we used here an evolutionary epigenetics approach building on differentially methylated regions (DMRs) of the genome.

Methods

We implemented a polygenic enrichment testing pipeline using the summary statistics of genome-wide association studies (GWAS) of schizophrenia and 12 other phenotypes. We investigated the enrichment of association of these traits across genomic regions with variable methylation between modern humans and great apes (orangutans, chimpanzees and gorillas; primate DMRs) and between modern humans and recently extinct hominids (Neanderthals and Denisovans; non-primate DMRs).

Results

Regions that are hypo-methylated in humans compared to great apes show enrichment of association with schizophrenia only if the major histocompatibility complex (MHC) region is included. With the MHC region removed from the analysis, only a modest enrichment for SNPs of low effect persists. The INRICH pipeline confirms this finding after rigorous permutation and bootstrapping procedures.

Conclusion

The analyses of regions with differential methylation changes in humans and great apes do not provide compelling evidence of enrichment of association with schizophrenia, in contrast to our previous findings on more recent methylation differences between modern humans, Neanderthals and Denisovans. Our results further support the evolutionary hypothesis of schizophrenia and indicate that the origin of some of the genetic susceptibility factors of schizophrenia may lie in recent human evolution.
A potential role for GrgA in regulation of σ28-dependent transcription in the obligate intracellular bacterial pathogen Chlamydia trachomatis
Authors: Desai Malhar , Wurihan Wurihan , Di Rong , Fondell Joseph D. , Nickels Bryce E. , Bao Xiaofeng , Fan Huizhou
Published: May 2018

The sexually transmitted obligate intracellular bacterial pathogen Chlamydia trachomatis has a unique developmental cycle consisting of two contrasting cellular forms. Whereas the primary Chlamydia sigma factor, σ66, is involved in the expression of the majority of chlamydial genes throughout the developmental cycle, expression of several late genes requires the alternative sigma factor σ28. In prior work we identified GrgA as a Chlamydia-specific transcription factor that activates σ66-dependent transcription by binding DNA and interacting with a non-conserved region (NCR) of σ66. Here, we extend these findings by showing GrgA can also activate σ28-dependent transcription through direct interaction with σ28. We measure the binding affinity of GrgA for both σ66and σ28, and we identify regions of GrgA important for σ28-dependent transcription. Similar to results obtained with σ66, we find that GrgA’s interaction with σ28 involves a NCR located upstream of conserved region 2 of σ28. Our findings suggest GrgA is an important regulator of both σ66- and σ28-dependent transcription in C. trachomatis and further highlight NCRs of bacterial RNA polymerase as targets for regulatory factors unique to particular organisms.
Kaposi’s sarcoma-associated herpesvirus ORF68 is a DNA binding protein required for viral genome cleavage and packaging
Authors: Gardner Matthew R , Glaunsinger Britt A
Published: May 2018

Herpesviral DNA packaging into nascent capsids requires multiple conserved viral proteins that coordinate genome encapsidation. Here, we investigated the role of the ORF68 protein of Kaposi’s sarcoma-associated herpesvirus (KSHV), a protein required for viral DNA encapsidation whose function remains largely unresolved across the herpesviridae. We found that KSHV ORF68 is expressed with early kinetics and localizes predominantly to viral replication compartments, although it is dispensable for viral DNA replication and gene expression. However, in agreement with its proposed role in viral DNA packaging, KSHV-infected cells lacking ORF68 failed to cleave viral DNA concatemers, accumulated exclusively immature B-capsids, and released no infectious progeny virions. ORF68 has no predicted domains aside from a series of putative zinc finger motifs. However,in vitrobiochemical analyses of purified ORF68 protein revealed that it robustly binds DNA and is associated with nuclease activity. These activities provide new insights into the role of KSHV ORF68 in viral genome encapsidation.

Importance

Kaposi’s sarcoma-associated herpesvirus (KSHV) is the etiologic agent of Kaposi’s sarcoma and several B-cell cancers, causing significant morbidity and mortality in immunocompromised individuals. A critical step in the production of infectious viral progeny is the packaging of the newly replicated viral DNA genome into the capsid, which involves coordination between at least seven herpesviral proteins. While the majority of these packaging factors have been well studied in related herpesviruses, the role of the KSHV ORF68 protein and its homologs remains unresolved. Here, using a KSHV mutant lacking ORF68, we confirm its requirement for viral DNA processing and packaging in infected cells. Furthermore, we show that the purified ORF68 protein directly binds DNA and is associated with a metal-dependent cleavage activity on double stranded DNAin vitro. These activities suggest a novel role for ORF68 in herpesviral genome processing and encapsidation.
Effective soil extraction method for cultivating previously uncultured soil bacteria
Authors: Manh Nguyen Tuan , Seo Chan , Ji Moongi , Paik Man-Jeong , Myung Seung-Woon , Kim Jaisoo
Published: May 2018

Here, a new medium named as intensive soil extract medium (ISEM) based on new soil extract (NSE) using 80% ethanol was used to efficiently isolate previously uncultured bacteria and new taxonomic candidates, which accounted for 49% and 55% of the total isolates examined (n=258), respectively. The new isolates were affiliating with seven phyla such asProteobacteria, Acidobacteria, Firmicutes, Actinobacteria, Verrucomicrobia, Planctomycetes, andBacteroidetes. The result of chemical analysis showed that NSE included more diverse components of low-molecular-weight organic substances than two conventional soil extracts using distilled water. Cultivation of previously uncultured bacteria is expected to extend knowledge through the discovery of new phenotypic, physiological and functional properties, and even roles of unknown genes.

IMPORTANCE

Either metagenomics or single-cell sequencing can detect unknown genes from uncultured microbial strains in environments and may find their significant potential metabolites and roles. However, such gene/genome-based techniques still have a critical problem making impossible for further applications through cultivation. To solve this problem, various approaches for cultivation of uncultured bacteria have been developed, but they still have lack of skill to grow them on solid media for isolation and subculture.
Validation of novelMycobacterium tuberculosisisoniazid resistance mutations not detectable by common molecular tests
Authors: Kandler Justin L. , Mercante Alexandra D. , Dalton Tracy L. , Ezewudo Matthew N. , Cowan Lauren S. , Burns Scott P. , Metchock Beverly ,   Global PETTS Investigatorsc, Cegielski Peter , Posey James E.
Published: May 2018

Resistance to the first-line anti-tuberculosis (TB) drug, isoniazid (INH), is widespread, and the mechanism of resistance is unknown in approximately 15% of INH-resistant (INH-R) strains. To improve molecular detection of INH-R TB, we used whole genome sequencing (WGS) to analyze 52 phenotypically INH-RMycobacterium tuberculosiscomplex (MTBC) clinical isolates that lacked the commonkatGS315T orinhApromoter mutations. Approximately 94% (49/52) of strains had mutations at known INH-associated loci that were likely to confer INH resistance. All such mutations would be detectable by sequencing more DNA adjacent to existing target regions. Use of WGS minimized the chances of missing infrequent INH resistance mutations outside commonly targeted hotspots. We used recombineering to generate 12 observed clinicalkatGmutations in the pansusceptible H37Rv reference strain and determined their impact on INH resistance. Our functional genetic experiments have confirmed the role of seven suspected INH resistance mutations and discovered five novel INH resistance mutations. All recombineeredkatGmutations conferred resistance to INH at a minimum inhibitory concentration of ≥0.25 μg/mL and should be added to the list of INH resistance determinants targeted by molecular diagnostic assays. We conclude that WGS is a superior method for detection of INH-R MTBC compared to current targeted molecular testing methods and could provide earlier diagnosis of drug-resistant TB.
Clinical scoring is the most sensitive biomarker detecting developing sepsis in newborn mice
Authors: Fehlhaber Beate , Rübensam Kathrin , Heinemann Anna S. , Pfeifer Sandra , von Köckritz-Blickwede Maren , Viemann Dorothee
Published: May 2018

Newborn individuals are highly susceptible to infectious diseases. For better insights into age-specific host-pathogen interactions infection models are increasingly employed in neonatal mice. However, for newborn mice no measures are available to objectify the clinical disease state, particularly not in a longitudinal manner, to meet legal animal welfare requirements. We developed a scoring system for newborn mice that relies on observational and examination-based parameters and validated it by applying aStaphylococcus aureus-induced infection model in two different mouse strains.

The scoring results strongly correlated with the death kinetics independent of which mouse strain was used. A score above 7 predicted fatality. While the score values increased already at early sepsis stages the large majority of plasma cytokine levels remained comparable to those in uninfected control neonates. The levels of interleukin (Il)-6, chemokine C-C motif ligand 5, Il-1α and tumor necrosis factor α were not increased before 24 hours after infection and correlated only at this late stage of sepsis with the scored disease state.

We propose the first clinical scoring system that serves as important research tool to evaluate the clinical course of sepsis in newborn mice. It detects health impairments of newborn pups in a highly sensitive and longitudinal manner, providing information about the disease severity as well as prognosis.
Lethality of leptospirosis depends on sex: male hamsters succumb to infection with lower doses of pathogenic Leptospira
Authors: Gomes Charles K. , Guedes Mariana , Potula Hari-Hara , Dellagostin Odir A. , Gomes-Solecki Maria
Published: May 2018

Leptospirosis is a widespread zoonotic disease caused by pathogenic spirochetes of the genus Leptospira which affect both humans and animals. A somewhat contradictory published body of evidence suggests that sex impacts severity outcomes of human Leptospirosis. In this study, we used an acute animal model of disease to analyze how male and female hamsters infected side-by-side with low but increasing doses of L. interrogans under the same exposure conditions develop Leptospirosis. We found that female hamsters were considerably more resistant to Leptospirosis given that 87.5% survived infection; male hamsters did not gain weight and 93.7% succumbed to infection with the same infectious doses. Analysis of bacterial burden in kidney of male hamsters showed that infection with the lowest dose (103) resulted in a 4Log increase of L. interrogans, whereas females infected with the same dose had a reduction of ~1Log, after 28 days of infection. Non-surviving hamsters had signs of compromised renal function (higher levels of creatinine in blood), as well as increased levels of anti-inflammatory IL-10 and innate response pro-inflammatory CCL3, CxCL10 and TNF-α in kidney, as well as ColA1 which is a marker of kidney fibrosis. In endemic areas, humans are more often exposed to the lower infection doses which were lethal to males, than the higher doses which were lethal to males and females. It is possible that the frequency of lower infectious doses in nature and increased biological susceptibility both contribute for aggravated outcomes of leptospirosis in males.
The Repertoire of Mutational Signatures in Human Cancer
Authors: Alexandrov Ludmil B , Kim Jaegil , Haradhvala Nicholas J , Huang Mi Ni , Ng Alvin WT , Wu Yang , Boot Arnoud , Covington Kyle R , Gordenin Dmitry A , Bergstrom Erik N , Islam S M Ashiqul , Lopez-Bigas Nuria , Klimczak Leszek J , McPherson John R , Morganella Sandro , Sabarinathan Radhakrishnan , Wheeler David A , Mustonen Ville ,   the PCAWG Mutational Signatures Working Group, Getz Gad , Rozen Steven G , Stratton Michael R
Published: May 2018

Somatic mutations in cancer genomes are caused by multiple mutational processes each of which generates a characteristic mutational signature. Using 84,729,690 somatic mutations from 4,645 whole cancer genome and 19,184 exome sequences encompassing most cancer types we characterised 49 single base substitution, 11 doublet base substitution, four clustered base substitution, and 17 small insertion and deletion mutational signatures. The substantial dataset size compared to previous analyses enabled discovery of new signatures, separation of overlapping signatures and decomposition of signatures into components that may represent associated, but distinct, DNA damage, repair and/or replication mechanisms. Estimation of the contribution of each signature to the mutational catalogues of individual cancer genomes revealed associations with exogenous and endogenous exposures and defective DNA maintenance processes. However, many signatures are of unknown cause. This analysis provides a systematic perspective on the repertoire of mutational processes contributing to the development of human cancer including a comprehensive reference set of mutational signatures in human cancer.
LAESI mass spectrometry imaging as a tool to differentiate the root metabolome of native and range-expanding plant species
Authors: Kulkarni Purva , Wilschut Rutger A. , Verhoeven Koen J.F. , van der Putten Wim H. , Garbeva Paolina
Published: May 2018

Our understanding of chemical diversity in biological samples has greatly improved through recent advances in mass spectrometry (MS). MS-based-imaging (MSI) techniques have further enhanced this by providing spatial information on the distribution of metabolites and their relative abundance.

This study aims to employ laser-assisted electrospray ionization (LAESI) MSI as a tool to profile and compare the root metabolome of two pairs of native and range expanding plant species.

It has been proposed that successful range-expanding plant species, like introduced exotic invaders, have a novel, or a more diverse secondary chemistry. Although some tests have been made using aboveground plant materials, tests using root materials are rare. We tested the hypothesis that range-expanding plants possess more diverse root chemistries than native plant species.

To examine the root chemistry of the selected plant species, LAESI-MSI was performed in positive ion mode and data was acquired in a mass range of m/z 50-1200 with a spatial resolution of 100 µm. The acquired data was analyzed using in-house scripts, and differences in the spatial profiles were studied for discriminatory mass features.
The results revealed clear differences in the metabolite profiles amongst and within both pairs of congeneric plant species, in the form of distinct metabolic fingerprints. The use of ambient conditions and the fact that no sample preparation was required, established LAESI-MSI as an ideal technique for untargeted metabolomics and for direct correlation of the acquired data to the underlying metabolomic complexity present in intact plant samples.
1H MR Spectroscopy of the Motor Cortex Immediately following Transcranial Direct Current Stimulation at 7 Tesla
Authors: Ryan Kayla , Wawrzyn Krzysztof , Gati Joseph , Chronik Blaine A. , Wong Dickson , Duggal Neil , Bartha Robert
Published: May 2018

Transcranial direct current stimulation (tDCS) is a form of non-invasive brain stimulation that may modulate cortical excitability, metabolite concentration, and human behaviour. The supplementary motor area (SMA) has been largely ignored as a potential target for tDCS neurorehabilitation but is an important region in motor compensation after brain injury with strong efferent connections to the primary motor cortex (M1). The objective of this work was to measure tissue metabolite changes in the human motor cortex immediately following tDCS. We hypothesized that bihemispheric tDCS would change levels of metabolites involved in neuromodulation including N-acetylaspartate, glutamate, and creatine. In this single-blind, randomized, cross-over study, fifteen healthy adults aged 21-60 participated in two 7T MRI sessions, to identify changes in metabolite concentrations by magnetic resonance spectroscopy. Immediately after 20 minutes of tDCS, there were no significant changes in metabolite levels or metabolite ratios comparing tDCS to sham. However there was a trend toward increased NAA/tCr concentration (p=0.08) in M1 under the stimulating cathode. There was a strong, positive correlation between the change in the absolute concentration of NAA and the change in the absolute concentration of tCr (p<0.001) suggesting an effect of tDCS. Both NAA and creatine are important markers of neurometabolism. Our findings provide novel insight into the modulation of neural metabolites in the motor cortex immediately following application of bihemispheric tDCS.
White spot syndrome virus infection induces Caspase 1-mediated antiviral cell death in crustacean
Authors: Yang Geng , Wang Jiajia , Luo Tao , Wei Jun , Yang Yadong , Zhang Wenyuan , Zhang Xiaobo
Published: May 2018

In vertebrates, pyroptosis is an intensely inflammatory form of programmed cell death which is dependent on Caspase 1 activation and release of cytoplasmic cytokines including IL-1β. This death pathway is critical for controlling pathogenic infection by mobilizing immune cells and stimulating the development of adaptive immune response. In invertebrates, however, due to the lack of adaptive immune response, it is still elusive whether Caspase 1-dependent cell death pathway exists. In this study, our data showed that Caspase 1-mediated cell death was activated by white spot syndrome virus (WSSV) infection to control the virus in shrimp. Caspase 1 had a higher expression level in hemocytes and lymphoid-like organ in shrimp and WSSV infection was significantly promoted upon the inhibition of Caspase 1 enzymatic activity. IL-1β-like protein was identified as the substrate of Caspase 1 and its interaction with Caspase 1 was validated ectopically and endogenously. Moreover, IL-1β like protein was released into extracellular contents under WSSV infection and Prophenoloxidase system was activated, resulting in the reduction of WSSV copiesin vivo. Our data unraveled a previously unidentified mechanism through which Caspase 1-dependent cell death controlled virus infection in shrimp. Therefore, our study opened the possibility that an invertebrate cytokine network might be operative and regulate host defenses against virus infection as in vertebrates.

Author Summary

The elimination of infected cells by programmed cell death is considered as one of the most important anti-pathogen responses. Pyroptosis is one form of programmed cell death, which is mediated by Caspase 1 activation. Activated Caspase 1 can process the inactive precursors of interleukin 1β (IL-1β) into mature inflammatory cytokines to induce potent immune responses. Meanwhile, pyroptosis also induces morphologic changes, DNA fragmentation and chromatin condensation to destroy infected cells. However, due to the lack of efficient adaptive immune responses, it is still unclear whether Caspase 1-mediated cell death also exits and plays such an important role in defending hosts from pathogen invasion in invertebrates. In our data, Caspase 1 gene was characterized and Caspase 1-mediated cell death pathway was validated in shrimp. The Caspase 1-mediated cell death pathway was enhanced by white spot syndrome virus (WSSV) infection to control the virus in shrimp. IL-1β-like protein was cleaved by Caspase 1 and released into extracellular contents under WSSV infection to activate Prophenoloxidase system, leading to the reduction of WSSV copies in shrimp in vivo. On the other hand, silencing ofCaspase 1orIL-1β-likegene facilitated virus infection in shrimp. Our study indicated that Casapase-1-mediated cell death played an important antiviral role in shrimp against WSSV infection and opened the possibility that an invertebrate cytokine network might be operative.
Did a plant-herbivore arms race drive chemical diversity in Euphorbia?
Authors: Ernst M. , Nothias L.-F. , van der Hooft J. J. J. , Silva R. R. , Saslis-Lagoudakis C. H. , Grace O. M. , Martinez-Swatson K. , Hassemer G. , Funez L. A. , Simonsen H. T. , Medema M. H. , Staerk D. , Nilsson N. , Lovato P. , Dorrestein P. C. , Rønsted N.
Published: May 2018

The genus Euphorbia is among the most diverse and species-rich plant genera on Earth, exhibiting a near-cosmopolitan distribution and extraordinary chemical diversity, especially across highly toxic macro-and polycyclic diterpenoids. However, very little is known about drivers and evolutionary origins of chemical diversity within Euphorbia. Here, we investigate 43 Euphorbia species to understand how geographic separation over evolutionary time has impacted chemical differentiation. We show that the structurally highly diverse Euphorbia diterpenoids are significantly reduced in species native to the Americas, compared to the Eurasian and African continents, where the genus originated. The localization of these compounds to young stems and roots suggest ecological relevance in herbivory defense and immunomodulatory defense mechanisms match diterpenoid levels, indicating chemoevolutionary adaptation to reduced herbivory pressure.

One Sentence Summary

Global chemo-evolutionary adaptation of Euphorbia affected immunomodulatory defense mechanisms.
ATPase and protease domain movements in the bacterial AAA+ protease FtsH are driven by thermal fluctuations
Authors: Ruer Martine , Krainer Georg , Gröger Philip , Schlierf Michael
Published: May 2018

AAA+ proteases are essential players in cellular pathways of protein degradation. Elucidating their conformational behavior is key for understanding their reaction mechanism and, importantly, for elaborating our understanding of mutation-induced protease deficiencies. Here, we study the structural dynamics of the Thermotoga maritima AAA+ hexameric ring metalloprotease FtsH (TmFtsH). Using a single-molecule Förster resonance energy transfer approach to monitor ATPase and protease inter-domain conformational changes in real time, we show that TmFtsH—even in the absence of nucleotide—is a highly dynamic protease undergoing conformational transitions between five states on the second timescale in a sequential manner. Addition of ATP does not influence the number of states nor change the timescale of domain motions, but affects the state occupancy distribution leading to an inter-domain compaction. These findings suggest that thermal energy, but not chemical energy, provides the major driving force for conformational switching, while ATP, through a state reequilibration, introduces directionality into this process. The TmFtsH A359V mutation, a homolog of the human pathogenic A510V mutation of paraplegin (SPG7) causing hereditary spastic paraplegia (HSP), does not affect the dynamic behavior of the protease but impairs the ATP-coupled domain compaction and, thus, may account for protease malfunctioning and pathogenesis in HSP.
Filamentation and restoration of normal growth in E.coli using a combined CRISPRi sgRNA/antisense RNA approach
Authors: Mückl Andrea , Schwarz-Schilling Matthaeus , Fischer Katrin , Simmel Friedrich C.
Published: May 2018

CRISPR interference (CRISPRi) using dCas9/sgRNA is a powerful tool for the exploration and manipulation of gene functions. Here we quantify the reversible switching of crucial cellular processes by CRISPRi and an antisense RNA mechanism. Reversible induction of filamentous growth in E. coli has been recently demonstrated by controlling the expression levels of the bacterial cell division proteins FtsZ/FtsA via CRISPRi. If FtsZ falls below a critical level, cells cannot divide. However, the cells remain metabolically active and continue with DNA replication. We surmised that this makes them amenable to an inducible antisense RNA strategy to counteract FtsZ inhibition. We show that both static and inducible thresholds can adjust the characteristics of the switching process. Combining bulk data with single cell measurements, we clarify the role of bacterial heterogeneity and population dynamics for gene circuits affecting cell division. Filamentation is shown to strongly increase gene expression variability in the bacteria. Furthermore, we find reversible switching only in a small subpopulation of the bacteria, which takes over the population upon continued cell division. Successful restoration of division occurs faster in the presence of antisense sgRNAs than upon simple termination of CRISPRi induction.
A feed-forward relay integrates the regulatory activities of Bicoid and Orthodenticle via sequential binding to suboptimal sites
Authors: Datta Rhea R. , Ling Jia , Kurland Jesse , Ren Xiaotong , Xu Zhe , Yucel Gozde , Moore Jackie , Shokri Leila , Baker Isabel , Bishop Timothy , Struffi Paolo , Levina Rimma , Bulyk Martha L. , Johnston Robert J. , Small Stephen
Published: May 2018

The K50 (lysine at amino acid position 50) homeodomain (HD) protein Orthodenticle (Otd) is critical for anterior patterning and brain and eye development in most metazoans. In Drosophila melanogaster, another K50HD protein, Bicoid (Bcd), has evolved to replace Otd's ancestral function in embryo patterning. Bcd is distributed as a long-range maternal gradient and activates transcription of a large number of target genes, including otd. Otd and Bcd bind similar DNA sequences in vitro, but how their transcriptional activities are integrated to pattern anterior regions of the embryo is unknown. Here we define three major classes of enhancers that are differentially sensitive to binding and transcriptional activation by Bcd and Otd. Class 1 enhancers are initially activated by Bcd, and activation is transferred to Otd via a feed-forward relay (FFR) that involves sequential binding of the two proteins to the same DNA motif. Class 2 enhancers are activated by Bcd and maintained by an Otd-independent mechanism. Class 3 enhancers are never bound by Bcd, but Otd binds and activates them in a second wave of zygotic transcription. The specific activities of enhancers in each class are mediated by DNA motif variants preferentially bound by Bcd or Otd and the presence or absence of sites for cofactors that interact with these proteins. Our results define specific patterning roles for Bcd and Otd and provide mechanisms for coordinating the precise timing of gene expression patterns during embryonic development.
Dissociable contributions of the amygdala to the immediate and delayed effects of emotional arousal on memory
Authors: Schümann Dirk , Sommer Tobias
Published: May 2018

Emotional arousal enhances memory encoding and consolidation leading to better immediate and delayed memory. Although the central noradrenergic system and the amygdala play critical roles in both effects of emotional arousal, we have recently shown that these effects are at least partly independent of each other, suggesting distinct underlying neural mechanisms. Here we aim to dissociate the neural substrates of both effects in 70 female participants using an emotional memory paradigm to investigate how neural activity, as measured by fMRI, and a polymorphism in the α2B-noradrenoceptor vary for these effects. To also test whether the immediate and delayed effects of emotional arousal on memory are stable traits, we invited back participants who were a part of a large-scale behavioral memory study ∼3.5 yr ago. We replicated the low correlation of the immediate and delayed emotional enhancement of memory across participants (r = 0.16) and observed, moreover, that only the delayed effect was, to some degree, stable over time (r = 0.23). Bilateral amygdala activity, as well as its coupling with the visual cortex and the fusiform gyrus, was related to the preferential encoding of emotional stimuli, which is consistent with affect-biased attention. Moreover, the adrenoceptor genotype modulated the bilateral amygdala activity associated with this effect. The left amygdala and its coupling with the hippocampus was specifically associated with the more efficient consolidation of emotional stimuli, which is consistent with amygdalar modulation of hippocampal consolidation.
Reinforcement signaling of punishment versus relief in fruit flies
Authors: König Christian , Khalili Afshin , Ganesan Mathangi , Nishu Amrita P. , Garza Alejandra P. , Niewalda Thomas , Gerber Bertram , Aso Yoshinori , Yarali Ayse
Published: May 2018

Painful events establish opponent memories: cues that precede pain are remembered negatively, whereas cues that follow pain, thus coinciding with relief are recalled positively. How do individual reinforcement-signaling neurons contribute to this “timing-dependent valence-reversal?” We addressed this question using an optogenetic approach in the fruit fly. Two types of fly dopaminergic neuron, each comprising just one paired cell, indeed established learned avoidance of odors that preceded their photostimulation during training, and learned approach to odors that followed the photostimulation. This is in striking parallel to punishment versus relief memories reinforced by a real noxious event. For only one of these neuron types, both effects were strong enough for further analyses. Notably, interfering with dopamine biosynthesis in these neurons partially impaired the punishing effect, but not the relieving after-effect of their photostimulation. We discuss how this finding constraints existing computational models of punishment versus relief memories and introduce a new model, which also incorporates findings from mammals. Furthermore, whether using dopaminergic neuron photostimulation or a real noxious event, more prolonged punishment led to stronger relief. This parametric feature of relief may also apply to other animals and may explain particular aspects of related behavioral dysfunction in humans.
Applying quality tools to improve student retention supporting process: a case study from WOU
Authors: Chuah PohLean , Lim PengKeat
Published: May 2018

Purpose

Student retention is important in the management of any university especially one which is not financially independent. Administrators in such institutions need to investigate ways to improve the retention rate in order to avoid the loss of revenue. One of the methods is to ensure that students are able to follow their study pathway and complete their study on time instead of dropping out. The purpose of this paper is to establish a system that allows the university to monitor the progression of these students and highlight the need for counselling when necessary. It is also hoped that this paper helps to improve the student retention rate using quality analysis tools and add knowledge into factual-based problem-solving methodology.

Design/methodology/approach

This paper is a co-relational study based on secondary data. It is a continuous improvement method adopting the “plan-do-check-action” model. Quality analysis tools adopted are failure modes and effects analysis and process mapping, where both are the quality analysis tools commonly used in solving product design or assembly process issues in manufacturing. Using the case study of Wawasan Open University, the authors will adapt the aforesaid quality analysis tools from design and manufacturing sectors into an open distance learning education design. It is hoped that the identified process facilitates certain functions of the departments of the organisation to be more effective.

Findings

This paper provides a practical approach on the methods to improve the retention rate in a private higher education institute. Stakeholders are more willing to embrace the improvement when there is proper factual analysis to support the plans. A cross-departmental team is formed to brainstorm the various aspects of the process and the potential failure modes. In a resource-constrained environment, prioritisation is important to identify the high-impact problems. It is also important that a mechanism is available to deliver information to the area where decisions and actions can be made. The failure modes are prioritised systematically and the corresponding solutions installed. The end result is a system with the process that reduces interdepartmental inconsistency thus providing students with a clearer visibility of their study pathway so that they can complete their study on time instead of dropping out.

Research limitations/implications

This study is performed within the context of an institute. The generalisation is low. Other researchers are encouraged to explore further.

Practical implications

This paper provides some practical actions for the improvement of student retention in the university. It is hoped that other researchers will be attracted to explore further on using quality analysis tools to solve non-technical problems.

Originality/value

This paper provides a structured problem-solving method in a service-oriented organisation.
Audit fee trends from 2000 to 2014
Authors: Dey R. Mithu , Lim Lucy
Published: May 2018

Purpose

Setting audit fees is a persistent source of stress for auditors who must, on one hand, comply with the increasing government regulations that generally cause costs to rise; and on the other hand, respond to client pressures to keep audit fees down. In the post-scandal environment of Enron, WorldCom, and the demise of Arthur Andersen, policy makers have introduced additional costs for auditors by increasing regulations and creating a new industry watchdog – the Public Company Accounting Oversight Board (PCAOB). In this environment of constant pricing-cost tension for the auditor, the purpose of this paper is to examine audit fee trends over an extended period, 2000-2014.

Design/methodology/approach

The authors calculate the unexpected audit fees using the audit fee model. The authors examine audit fee trends while controlling for changes due to inflation, auditor wages, and other audit fee determinants.

Findings

The key findings indicate that audit fees increased in response to the promulgation of new audit regulations requiring additional audit work, the Sarbanes-Oxley (SOX) Act of 2002 and Auditing Standard No. 2 in 2004. Additionally, the authors find that audit fees decreased after new regulations alleviating audit work, namely the passage of Auditing Standard No. 5 in 2007, and remained unchanged when new regulations had a minimal impact on audit work, namely the Dodd-Frank Act of 2010.

Practical implications

The findings of this research are relevant to audit clients, auditors, and regulators as they weigh the cost and benefits of significant new audit regulations and their impacts on audit fees.

Originality/value

Using the more recent US data, the results in this paper show how events changed audit fee trends in recent years. The findings indicate that audit fees increased after the passage of new audit regulations such as the SOX Act of 2002, Auditing Standards No. 2 in 2004, and decreased after the passage of Auditing Standards No. 5 in 2007.
More entrepreneur innovation and less labor conflicts – empirical evidence from China employer–employee survey
Authors: Li Tang , Deng Yue , Jia Xu , Wang Zeyu
Published: May 2018

Purpose

Labor conflict has become a serious problem in recent China. From the perspective of entrepreneur innovation, this paper aims to find an effective path to eliminate this conflict. On the basis of theoretical analyses and regression analyses, this paper finds that, with legal environment and other conditions identical, entrepreneur innovation will significantly facilitate elimination of labor conflicts.

Design/methodology/approach

Using theoretical analyses based on entrepreneurship theory, this paper puts forward a series of hypotheses about the effects of entrepreneur innovation on labor conflicts. With panel data during 2013-2015 from China Employer–Employee Survey, this paper examines the effects of entrepreneur innovation on labor conflicts. Using interaction term regressions, this paper examines heterogeneous effects of entrepreneur innovation on labor conflicts by ownership, market power and export behavior. With mediating effect model, this paper examine whether workers’ participation in corporation governance is an important channel in which entrepreneurial innovation can impact on labor conflicts.

Findings

First, using benchmark regressions and robustness checks, this paper finds that there exist significantly positive effects of entrepreneur innovation on workers’ job satisfaction, incentive, social security, job development and job stability, which will reduce potential risks of labor conflict effectively. Second, using interaction term regressions, this paper finds that there exist heterogeneous effects of entrepreneur innovation on labor conflicts by ownership, market power and export behaviors. The study finds that the effects of entrepreneur innovation are more concentrated in private firms, firms with stronger market power and non-exporters. Third, using a mediating effect model, the study finds that workers’ participation in corporation governance is an important channel in which entrepreneur innovation can have impacts on labor conflicts.

Originality/value

The paper enriches the existing research about how to eliminate labor conflicts in China. On the basis of China Employer–Employee Survey data, this paper finds the importance of entrepreneur innovation on Chinese transition, which not only has positive impacts on firm performance, but also has impacts on eliminating labor conflicts and establishing better labor relationship. Therefore, stimulating entrepreneur innovation is very important for solving conflicts during Chinese transition.
Housing affordability in Malaysia: perception, price range, influencing factors and policies
Authors: Yap Jeffrey Boon Hui , Ng Xin Hua
Published: May 2018

Purpose

The purpose of this paper is to explore the affordability of Malaysian housing market, sufficiency of affordable housing and factors influencing the housing affordability in Malaysia.

Design/methodology/approach

In this study, qualitative research approach was adopted. Semi-structured interviews were conducted with ten industry practitioners from developers and real estate agencies and further validation with three industry experts.

Findings

The findings reveal that housing affordability is a grave concern to average Malaysians, and the supply of affordable housing is insufficient in the current residential property market. Income, property price, land cost and demand and supply are identified as significant factors affecting housing affordability.

Research limitations/implications

The research findings provide an insight rather than definitive information, as the small sample size could limit the generalizability of the findings. Future research can include participants from the public sector and focus on the policy options.

Practical implications

This paper provided numerous policies to ensure successful deliverability of affordable housing which eases government to partner with private sector to formulate a systematic framework for implementation of affordable housing programs and schemes.

Social implications

There is a need for government to pay more attention to housing needs of middle-income groups. Also, the government is urged to ensure transparent balloting process in every implementation of affordable housing programs.

Originality/value

The paper emphasised the issues of undersupply of affordable housing and mismatch of property price and income. The paper also highlights the key reasons behind high housing affordability index. Hence, it is hoped that this paper will encourage positive debate and gain some attention from the policymakers, practitioners and researchers in Malaysia and beyond.
Assessing the determinants of retirement home ownership among Malaysian young-old seniors
Authors: Tan Teck Hong , Lee Ji Hei
Published: May 2018

Purpose

Many of the existing senior living accommodation options in Malaysia are ill-suited to the needs and requirements of seniors as they age further. To establish best practice guidance to meet the housing needs for seniors, the purpose of this paper is to examine the effect of neighbourhood quality, locational and structural attributes on the likelihood of owning a retirement home among the young-old aged 60 to 74 years in Malaysia.

Design/methodology/approach

In this paper, 300 young-old retirees from Greater Kuala Lumpur, Malaysia were interviewed using purposive sampling. Only 240 were used for the analysis.

Findings

The results revealed that respondents are likely to own the retirement home which could support their overall health and well-being within a safe and supportive senior-friendly neighbourhood. Furthermore, respondents are willing to reside in the retirement home that is served with good access to amenities.

Research limitations/implications

The likelihood of young-old seniors adjusting their housing disequilibrium situation is higher as long as the right housing attributes are incorporated into the retirement home.

Practical implications

The results of this paper would be very pertinent for the development of the physical planning guidelines on settlements and facilities for the elderly in Malaysia.

Originality/value

With the change in cultural values, the increasing life expectancy in senior adult population and improved household income in Malaysia, there is great potential for purpose-built senior housing projects for seniors who need help with activities of daily living, but desire to live as independently as possible.
Competitive vs coopetitive strategies: lessons from professional sport leagues
Authors: Fulconis François , Nollet Jean , Paché Gilles
Published: May 2018

Purpose

Over the past decades, analyses of the functioning of professional sport leagues have been done from various angles: economic, financial and sociological; in some cases, comparisons were made between North-American and European leagues. The purpose of this paper is to look at this reality from a different angle, i.e. human capital management, by showing how different the models from both continents are.

Design/methodology/approach

Based on an identification of the major elements associated to human capital management in professional sport leagues in North America and Europe, this paper compares competitive and coopetitive strategies using an original framework based on consortium sourcing and pooling dimensions.

Findings

The paper underlines the benefits that North-American professional sport leagues get from acquiring players using a consortium sourcing perspective (coopetition). In Europe, the most powerful clubs use their financial resources to get the best players; as a result, it is always the same clubs with get the best results (competition). In the long run, the European approach might result in less attractiveness to TV viewers, and less revenues for TV networks.

Originality/value

This paper helps to understand the differences between professional sport leagues in North America and Europe; it also discusses the risk associated to the adoption, without any adjustment in the human capital management, in Europe of the North-American model based on a coopetitive perspective. This dimension is seldom mentioned in articles dealing with professional sport leagues.