bluuebunny/crossref_metadata_2025 huggingface dataset:
The receptor PTPRU is a redox sensitive pseudophosphatase
Authors: Hay Iain M. , Fearnley Gareth W. , Rios Pablo , Köhn Maja , Sharpe Hayley J. , Deane Janet E.
Published: October 2019

The dynamic regulation of protein tyrosine phosphorylation is a critical feature of intercellular communication and is regulated by the actions of kinases and phosphatases. The receptor-linked protein tyrosine phosphatases (RPTPs) are key signaling molecules that possess an extracellular domain and intracellular phosphatase domains. Most human RPTPs have tandem intracellular tyrosine phosphatase domains: a catalytically active membrane proximal (D1) domain; and a membrane distal (D2) inactive “pseudophosphatase” domain. The receptor PTPRU plays a role in development, multiple cancers and has been implicated in the dephosphorylation of cell adhesion proteins. However, PTPRU has a non-canonical D1 domain containing several sequence variations in key catalytic loops that suggest it may function using a mechanism distinct from related RPTPs. Here, we demonstrate through biochemical and structural studies that PTPRU is unique amongst the RPTPs in possessing two pseudophosphatase domains. We show that PTPRU-D1 displays no detectable catalytic activity against a range of phosphorylated substrates and determine that this is due to substantial disorder in the substrate-binding pocket as well as rearrangement of the catalytic loop such that the active site cysteine is occluded. We also show that this cysteine can form an intramolecular disulfide bond with a vicinal “backdoor” cysteine. Further, we demonstrate that the PTPRU D2 domain can recruit substrates of related RPTPs suggesting that this pseudophosphatase functions by competing with active phosphatases for the binding of substrates involved in cell adhesion. Therefore, PTPRU is abona-fidepseudophosphatase and its functional role in cell signaling is via a non-catalytic mechanism.

SIGNIFICANCE STATEMENT

Protein tyrosine phosphorylation is a key post-translational modification required for cellular communication that is dynamically regulated by the activities of tyrosine kinases and phosphatases. Receptor tyrosine phosphatases (RPTPs) possess an extracellular receptor domain and intracellular phosphatase domains. We show that PTPRU is a non-canonical RPTP devoid of catalytic activity and demonstrate that this is due to multiple structural rearrangements. Despite this, PTPRU retains the capacity to bind the substrates of related phosphatases suggesting that the non-catalytic function of this pseudophosphatase is to compete with active phosphatases for the binding of substrates. Such pseudoenzymes represent an exciting and growing area of research with implications as key regulators of signaling networks.
Natural selection drives population divergence for local adaptation in a wheat pathogen
Authors: Pereira Danilo , Croll Daniel , Brunner Patrick C. , McDonald Bruce A.
Published: October 2019

Evolution favors the emergence of locally-adapted optimum phenotypes that are likely to differ across a wide array of environmental conditions. The emergence of favorable adaptive characteristics is accelerated in agricultural pathogens due to the unique properties of agro-ecosystems. We performed a QST- FSTcomparison using 164 strains ofParastagonospora nodorumsampled from eight global field populations to disentangle the predominant evolutionary forces driving population divergence in a wheat pathogen. We used digital image analysis to obtain quantitative measurements of growth rate and melanization at different temperatures and under different fungicide concentrations in a common garden experiment. FSTmeasures were based on complete genome sequences obtained for all 164 isolates. Our analyses indicated that all measured traits were under selection. Growth rates at 18°C and 24°C were under stabilizing selection (QST< FST), while diversifying selection (QST> FST) was the predominant evolutionary force affecting growth under fungicide and high temperature stress. Stabilizing selection (QST< FST) was the predominant force affecting melanization across the different environments. Melanin production increased at 30°C but was negatively correlated with higher growth rates, consistent with a trade-off under heat stress. Our results demonstrate that global populations ofP. nodorumpossess significant evolutionary potential to adapt to changing local conditions, including warmer temperatures and applications of fungicides.
Vector Trace cells in the Subiculum of the Hippocampal formation
Authors: Poulter Steven , Lee Sang Ah , Dachtler James , Wills Thomas J. , Lever Colin
Published: October 2019

Successfully navigating in physical or semantic space requires a neural representation of allocentric (map-based) vectors to boundaries, objects, and goals. Cognitive processes such as path-planning and imagination entail recall of vector representations, but evidence of neuron-level memory for allocentric vectors has been lacking. Here we describe a novel neuron type (Vector Trace cell, VTC) whose firing generates a new vector field when a cue is encountered, and also a ‘trace’ version of that field for hours after cue removal. VTCs are concentrated in subiculum distal to CA1. Compared to non-trace cells, VTCs fire at further distances from cues, and exhibit earlier-going shifts in preferred theta phase in response to newly introduced cues, demonstrating a theta-linked neural substrate for memory encoding. VTCs suggest a vector-based model of computing spatial relationships between an agent and multiple spatial objects, or between different objects, freed from the constraints of direct perception of those objects.
Rare species perform worse than common species under changed climate
Authors: Vincent Hugo , Bornand Christophe N. , Kempel Anne , Fischer Markus
Published: October 2019

Predicting how species, particularly rare and endangered ones, will react to climate change is a major current challenge in ecology. Rare species are expected to have a narrower niche width than common species. However, we know little whether they are also less able to cope with new climatic conditions. To simulate climate change, we transplanted 35 plant species varying in rarity to five botanical gardens in Switzerland, differing in altitude. For each species we calculated the difference in climate between their natural habitats and the novel climate of the respective botanical garden. We found that rare species had generally lower survival and biomass production than common species. Moreover, rare plant species survived less when the amount of precipitation differed more from the one in their natural range, indicating a higher susceptibility to climate change. Common species, in contrast, survived equally well under all climates and even increased their biomass under wetter or drier conditions. Our study shows that rarer species are less able to cope with changes in climate compared to more widespread ones, which might even benefit from these changes. This indicates that already rare and endangered plant species might suffer strongly from future climate change.
Press disturbance unveils different community structure, function and assembly of bacterial taxa and functional genes in mesocosm-scale bioreactors
Authors: Santillan E. , Constancias F. , Wuertz S.
Published: October 2019

Sustained perturbations, or press disturbances, are of interest in microbial ecology as they can drive systems to alternative stable states. Here, we tested the effect of a sustained doubling of organic carbon loading on structure, assembly and function of bacterial communities. Two sets of replicate 5-liter sequencing batch reactors were operated at two different organic carbon loading levels (323 and 629 mg COD L-1) for a period of 74 days, following 53 days of acclimation after inoculation with sludge from a full-scale treatment plant. Temporal dynamics of community taxonomic and functional gene structure were derived from metagenomics and 16S rRNA gene metabarcoding data. Assembly mechanisms were assessed through a mathematical null model on the effective bacterial turnover expressed as a proportion of total bacterial diversity. Disturbed reactors exhibited different community function, structure and assembly compared to the undisturbed reactors. Bacterial taxa and functional genes showed dissimilar alpha-diversity and community assembly patterns. Deterministic assembly mechanisms were generally stronger in disturbed reactors, associated with common taxa. Stochastic assembly was more important for functional genes and was driven by rare genes. We urge caution when assessing microbial community assembly mechanisms, as results can vary depending on the approach.
How beat perception coopts motor neurophysiology
Authors: Cannon Jonathan J. , Patel Aniruddh D.
Published: October 2019

Beat perception is central to music cognition. The motor system is involved in beat perception, even in the absence of movement, yet current frameworks for modeling beat perception do not strongly engage with the motor system’s neurocomputational properties. We believe fundamental progress on modeling beat perception requires a synthesis between cognitive science and motor neuroscience, yielding predictions to guide research. Success on this front would be a landmark in the study of how “embodied cognition” is implemented in brain activity. We illustrate this approach by proposing specific roles for two key motor brain structures (the supplementary motor area, and the dorsal striatum of the basal ganglia) in covert beat maintenance, building on current research on their role in actual movement.

Highlights

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Components of the brain’s motor system are activated by the perception of a musical beat, even in the absence of movement, and may play an important role in beat-based temporal prediction.

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Two key brain regions involved in movement, the supplementary motor area and dorsal striatum, have neurocomputational properties that lend themselves to beat perception.

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In supplementary motor area, neural firing rates represent the phase of cyclic sensorimotor processes.

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Supplementary motor area’s involvement in perceptual suppression of self-generated sounds suggests that it could play a broader role in informing auditory expectations.

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Dorsal striatum plays a central role in initiating and sequencing units of movement, and may serve similar functions in structuring beat-based temporal anticipation.
A simple mass-action model predicts genome-wide protein timecourses from mRNA trajectories during a dynamic response in two strains ofSaccharomyces cerevisiae
Authors: Kuo Sidney , Egertson Jarrett D. , Merrihew Gennifer E. , MacCoss Michael J. , Pollard Daniel A. , Rifkin Scott A.
Published: October 2019

Although mRNA is a necessary precursor to protein, several studies have argued that the relationship between mRNA and protein levels is often weak. This claim undermines the functional relevance of conclusions based on quantitative analyses of mRNA levels, which are ubiquitous in modern biology from the single gene to the whole genome scale. Furthermore, if post-translational processes vary between strains and species, then comparative studies based on mRNA alone would miss an important driver of diversity. However, gene expression is dynamic, and most studies examining relationship between mRNA and protein levels at the genome scale have analyzed single timepoints. We measure yeast gene expression after pheromone exposure and show that, for most genes, protein timecourses can be predicted from mRNA timecourses through a simple, gene-specific, generative model. By comparing model parameters and predictions between strains, we find that while mRNA variation often leads to protein differences, evolution also manipulates protein-specific processes to amplify or buffer transcriptional regulation.
Dopamine and risky decision-making in pathological and problem gamblers
Authors: Peters Jan , Vega Taylor , Weinstein Dawn , Mitchell Jennifer , Kayser Andrew
Published: October 2019

Gambling disorder is a behavioral addiction that is associated with impairments in value-based decision-making such as increased temporal discounting and reduced risk-aversion. Dopamine regulates learning and decision-making by modulating information processing throughout fronto-striatal circuits. Although the role of alterations in dopamine neurotransmission in the etiology of gambling disorder is controversial, preliminary evidence suggests that specifically increasing frontal dopamine levels might improve cognitive functioning in pathological and problem gamblers. We therefore examined whether increasing frontal dopamine levels via the catechol-O-methyltransferase (COMT) inhibitor tolcapone would reduce risky choice in a group of pathological and problem gamblers (n=14) in a repeated-measures counter-balanced placebo-controlled double-blind study. Choice data were fit using hierarchical Bayesian parameter estimation and a modeling scheme that combined a risky choice model with the drift diffusion model to account for both choices and response time distributions. Model comparison revealed that the data were best accounted for by a variant of the drift diffusion model with a non-linear modulation of trial-wise drift rates by value differences, confirming recent findings. Contrary to our hypothesis, risk-taking was slightly increased under tolcapone vs. placebo (Cohen’s d= −.281). Examination of drug effects on diffusion model parameters revealed an increase in the value-dependency of the drift rate (Cohen’s d= .932) with a simultaneous reduction in the maximum drift rate (Cohen’s d= −1.84). These results add to previous work on the potential role of COMT inhibitors in behavioral addictions, and show no consistent beneficial effect of tolcapone on risky choice in gambling disorder. Modeling results add to mounting evidence for the applicability of diffusion models in value-based decision-making. Future work should focus on individual genetic, clinical and cognitive factors that might account for the heterogeneity in the effects of COMT inhibition.
Reference transcriptome data in silkwormBombyx mori
Authors: Yokoi Kakeru , Tsubota Takuya , Jouraku Akiya , Sezutsu Hideki , Bono Hidemasa
Published: October 2019

Background

The silkwormBombyx moriis a lepidopteran model insect with biological and industrial importance. Its high-quality genome sequence has recently become available and the utilization of this information in combination with extensive transcriptomic analyses is expected to provide an elaborate gene model. It will also be possible to clarify gene expression in detail using this approach.

Results

We herein performed RNA-seq analysis of ten major tissues/subparts of silkworm larvae. Sequences were mapped onto the reference genome assembly and reference transcriptome data was successfully constructed. The reference data provided a nearly complete sequence forsericin-1, a major silk gene with a complex structure. We also markedly improved the gene model for other genes. Transcriptomic expression was investigated in each tissue and a number of transcripts were identified that were exclusively expressed in tissues such as the testis. Transcripts strongly expressed in the midgut formed tight genomic clusters, suggesting that they originated from tandem gene duplication. Transcriptional factor genes expressed in specific tissues or the silk gland subparts were also identified.

Conclusions

We successfully constructed reference transcriptome data in the silkworm and found that a number of transcripts showed unique expression profiles. These results will facilitate basic studies on the silkworm and accelerate its applications, which will contribute to further advances in lepidopteran and entomological research and the practical use of these insects.
A Mean-Field Description of Bursting Dynamics in Spiking Neural Networks with Short-Term Adaptation
Authors: Gast R. , Schmidt H. , Knösche T.R.
Published: October 2019

Bursting plays an important role in neural communication. At the population level, macro-scopic bursting has been identified in populations of neurons that do not express intrinsic bursting mechanisms. For the analysis of such phase transitions, mean-field descriptions of macroscopic bursting behavior pose a valuable tool. In this article, we derive mean-field descriptions of populations of spiking neurons in which collective bursting behavior arises via short-term adaptation mechanisms. Specifically, we consider synaptic depression and spike-frequency adaptation in networks of quadratic integrate-and-fire neurons. We characterize the emerging bursting behavior using bifurcation analysis and validate our mean-field derivations by comparing the microscopic and macroscopic descriptions of the population dynamics. Hence, we provide mechanistic descriptions of phase transitions between bursting and non-bursting population dynamics which play important roles in both healthy neural communication and neurological disorders.
Anatomically remote education of B cells is required for colonic health
Authors: Surana Neeraj K. , Couter Cheryn J. , Alvarez David , von Andrian Uli H. , Kasper Dennis L.
Published: October 2019

Mucosa-associated lymphoid tissues contain roughly 80% of all immune cells and produce virtually all of the body’s IgA1–3. Although the majority of IgA-secreting cells educated within a mucosal site home back to the same anatomic region, some cells are also found in distant mucosal tissues2–6. These observations underlie the notion of a common mucosal immune system, which holds that anatomically unrelated mucosal sites are functionally connected by a shared immune system2,3. However, the ontological basis of this separation between site of immune education and functionality has remained elusive. Here we show that mice lacking Peyer’s patches (PPs)—small-intestinal lymphoid tissue covered by antigen-sampling M cells—have no immunologic defect in the small-intestinal lamina propria. Surprisingly, the primary immunological abnormality in PP-deficient mice was a reduction in colonic B cells, including plasmablasts but not plasma cells. Adoptive transfer experiments conclusively demonstrated that PP-derived cells preferentially give rise to colonic—but not small-intestinal—B cells and plasmablasts. Finally, these PP-derived colonic B cells were critical for restraining colonic inflammation. Thus, PPs bridge the small-intestinal and colonic immune systems and provide a clear example of immune education being required in an anatomic compartment distinct from the effector site. Our findings, which highlight that the majority of fecal IgA is produced by colonic plasmablasts that originate from PPs, will help inform design of mucosal vaccines.
Lymphoid follicle formation and human vaccination responses recapitulated in an organ-on-a-chip
Authors: Goyal G. , Prabhala P. , Mahajan G. , Bausk B. , Gilboa T. , Xie L. , Zhai Y. , Lazarovits R. , Mansour A. , Kim Min Sun , Curran D. , Long J. M. , Sharma S. , Cohen L. , Levy O. , Prantil-Baun R. , Walt D.R. , Ingber D.E.
Published: October 2019

Lymphoid follicles (LFs) are responsible for generation of adaptive immune responses in secondary lymphoid organs and form ectopically during chronic inflammation. A human model of LF formation would provide a tool to understand LF development and an alternative to non-human primate models for preclinical evaluation of vaccines. Here, we show that primary human blood B- and T-lymphocytes autonomously assemble into ectopic LFs when cultured in a three-dimensional (3D) extracellular matrix gel within an organ-on-a-chip microfluidic device. Dynamic fluid flow is required for LF formation and prevention of lymphocyte autoactivation. These germinal center-like LFs contain B cells expressing Activation-Induced Cytidine Deaminase and exhibit plasma cell (PC) differentiation upon activation. To explore their utility for vaccine testing, autologous monocyte-derived dendritic cells were integrated into LF Chips. The human LF chips demonstrated improved antibody responses to split virion influenza vaccination compared to 2D cultures, which were enhanced by addition of a squalene-in-water emulsion adjuvant, and this was accompanied by increases in LF size and number. When inoculated with commercial influenza vaccine, PC formation and production of anti-hemagglutinin IgG were observed, as well as secretion of cytokines similar to those observed in vaccinated humans over clinically relevant timescales.
Assessing exposure effects on gene expression
Authors: Reifeis Sarah A. , Hudgens Michael G. , Civelek Mete , Mohlke Karen L. , Love Michael I.
Published: October 2019

In observational genomics datasets, there is often confounding of the effect of an exposure on gene expression. To adjust for confounding when estimating the exposure effect, a common approach involves including potential confounders as covariates with the exposure in a regression model of gene expression. However, when the exposure and confounders interact to influence gene expression, the fitted regression model does not necessarily estimate the overall effect of the exposure. Using inverse probability weighting (IPW) or the parametric g-formula in these instances is straightforward to apply and yields consistent effect estimates. IPW can readily be integrated into a genomics data analysis pipeline with upstream data processing and normalization, while the g-formula can be implemented by making simple alterations to the regression model. The regression, IPW, and g-formula approaches to exposure effect estimation are compared herein using simulations; advantages and disadvantages of each approach are explored. The methods are applied to a case study estimating the effect of current smoking on gene expression in adipose tissue.
A Computational Model of Thalamic Tonic-burst Motor Projection Neurons and Their Regulation by Pallidal GABAergic Neurons
Authors: Azam Md Ali , Kumbhare Deepak , Hadimani Ravi , Toms Jamie , Baron Mark S. , Atulasimha Jayasimha
Published: October 2019

A modified computational model of pallidal receiving ventral oral posterior (Vop) thalamocortical motor relay neurons was adapted based on in vivo observations in our rodent model. The model accounts for different input neuronal firing patterns in the primary motor output nucleus of basal ganglia, the globus pallidus interna (GPi) and subsequently generate Vop outputs as observed in vivo under different conditions. Hyperpolarizing input de-inactivates its T-type calcium channel and sets the thalamic neurons in the preferable burst firing mode over a tonic mode and induces low threshold spikes (LTS). In the hyperpolarized state, both spontaneously and in response to excitatory (e.g. corticothalamic) inputs, burst spiking occurs on the crest of the LTS. By selecting and determining the timing and extent of opening of thalamic T-type calcium channels via GABAergic hyperpolarizing input, the GPi precisely regulates Vop-cortical burst motor signaling. Different combinations of tonic, burst, irregular tonic and irregular burst inputs from GPi were used to verify our model. In vivo data obtained from recordings in the entopedunucular nucleus (EP; rodent equivalent of GPi) from resting head restrained healthy and dystonic rats were used to simulate the influences of different inputs from GPi. In all cases, GPi neuronal firing patterns are demonstrated to act as a firing mode selector for thalamic Vop neurons.
Dynamic Transcriptome, Accessible Genome and PGR Cistrome Profiles in the Human Myometrium
Authors: Wu San-Pin , Anderson Matthew L. , Wang Tianyuan , Zhou Lecong , Emery Olivia M. , Li Xilong , DeMayo Francesco J.
Published: October 2019

The myometrium undergoes structural and functional remodeling during pregnancy. We hypothesize that myometrial genomic elements alter correspondingly in preparation for parturition. Human myometrial tissues from nonpregnant (NP) and term pregnant (TP) human subjects were examined by RNAseq, ATACseq and PGR ChIPseq assays to profile transcriptome, assessible genome and PGR occupancy. NP and TP specimens exhibit 2890 differentially expressed genes, reflecting an increase of metabolic, inflammatory and PDGF signaling, among others, in adaptation to pregnancy. At the epigenome level, patterns of accessible genome change between NP and TP myometrium, leading to altered enrichment of binding motifs for hormone and muscle regulators such as the progesterone receptor (PGR), Krüppel-like factors and MEF2A transcription factors. PGR genome occupancy exhibits a significant difference between the two stages of the myometrium, concomitant with distinct transcriptomic profiles including genes such as ENO1, LHDA, and PLCL1 in the glycolytic and calcium signaling pathways. Over-representation of SRF, MYOD and STAT binding motifs in PGR occupying sites further suggests interactions between PGR and major muscle regulators for myometrial gene expression. In conclusion, changes in accessible genome and PGR occupancy are part of the myometrial remodeling process and may serve as mechanisms to formulate the state-specific transcriptome profiles.
CXCL4 links inflammation and fibrosis through transcriptional and epigenetic reprogramming of monocyte-derived cells
Authors: Silva-Cardoso Sandra C , Tao Weiyang , Angiolilli Chiara , Lopes Ana P. , Bekker Cornelis P.J. , Devaprasad Abhinandan , Giovannone Barbara , van Laar Jaap , Cossu Marta , Marut Wioleta , Hack Erik , de Boer Rob J , Boes Marianne , Radstake Timothy R.D.J. , Pandit Aridaman
Published: October 2019

Fibrosis is a condition shared by numerous inflammatory diseases. Our incomplete understanding of the molecular mechanisms underlying fibrosis has severely hampered effective drug development. CXCL4 is associated with the onset and extent of fibrosis development in systemic sclerosis, a prototypic inflammatory and fibrotic disease. Here, we integrated 65 paired longitudinal transcriptional and methylation profiles from monocyte-derived cells with/without CXCL4 exposure. Using data-driven gene regulatory network analyses, we demonstrate that CXCL4 dramatically alters the trajectory of monocyte differentiation, inducing a novel pro-inflammatory and pro-fibrotic phenotype mediated via key transcriptional regulators including CIITA. CXCL4 exposed monocyte-derived cells directly trigger a fibrotic cascade by producing ECM molecules and inducing myofibroblast differentiation. Inhibition of CIITA mimicked CXCL4 in inducing a pro-inflammatory and pro-fibrotic phenotype, validating the relevance of the gene regulatory network. Our study unveils CXCL4 as a key secreted factor driving innate immune training and forming the long-sought link between inflammation and fibrosis.
Opioids depress breathing through two small brainstem sites
Authors: Bachmutsky Iris , Wei Xin Paul , Kish Eszter , Yackle Kevin
Published: October 2019

The rates of opioid overdose in the United States quadrupled between 1999 and 2017, reaching a staggering 130 deaths per day. This health epidemic demands innovative solutions that require uncovering the key brain areas and cell types mediating the cause of overdose—opioid respiratory depression. Here, we identify two primary changes to breathing after administering opioids. These changes implicate the brainstem’s breathing circuitry which we confirm by locally eliminating the μ-Opiate receptor. We find the critical brain site is the origin of the breathing rhythm, the preBötzinger Complex, and use genetic tools to reveal that just 70-140 neurons in this region are responsible for its sensitivity to opioids. Future characterization of these neurons may lead to novel therapies that prevent respiratory depression while sparing analgesia.
Top-down feature-based cueing modulates conflict-specific ERP components in a Stroop-like task with equiprobable conditions
Authors: Galashan Daniela , Siemann Julia , Herrmann Manfred
Published: October 2019

Both attention and interference processing involve the selection of relevant information from incoming signals. Studies already show that interference decreases when the target location is precued correctly using spatial cueing. Complementary, we examine the effect of feature-based attentional cueing on interference processing. We used a design with equal stimulus probabilities where no response preparation was possible in the valid condition due to a response mapping alternation from trial to trial. The color of the Stroop stimuli was precued either validly or invalidly. Electrophysiological data (EEG) from 20 human participants are reported. We expected reduced interference effects with valid cueing for behavioral data and for both Stroop-associated event-related potential (ERP) components (N450 and sustained positive potential; SP). The N450 showed a significant effect for valid trials but no effect in the invalid condition. In contrast, the SP was absent with valid cueing and present with invalid cues. These findings suggest that focused feature-based attention leads to a more effective attentional selectivity. Furthermore, the top-down influence of feature-based attention differentially affects the N450 and SP components.
The RNA Atlas, a single nucleotide resolution map of the human transcriptome
Authors: Lorenzi Lucia , Chiu Hua-Sheng , Cobos Francisco Avila , Gross Stephen , Volders Pieter-Jan , Cannoodt Robrecht , Nuytens Justine , Vanderheyden Katrien , Anckaert Jasper , Lefever Steve , Goovaerts Tine , Hansen Thomas Birkballe , Kuersten Scott , Nijs Nele , Taghon Tom , Vermaelen Karim , Bracke Ken R. , Saeys Yvan , De Meyer Tim , Deshpande Nandan , Anande Govardhan , Chen Ting-Wen , Wilkins Marc R. , Unnikrishnan Ashwin , De Preter Katleen , Kjems Jørgen , Koster Jan , Schroth Gary P. , Vandesompele Jo , Sumazin Pavel , Mestdagh Pieter
Published: October 2019

The human transcriptome consists of various RNA biotypes including multiple types of non-coding RNAs (ncRNAs). Current ncRNA compendia remain incomplete partially because they are almost exclusively derived from the interrogation of small- and polyadenylated RNAs. Here, we present a more comprehensive atlas of the human transcriptome that is derived from matching polyA-, total-, and small-RNA profiles of a heterogeneous collection of nearly 300 human tissues and cell lines. We report on thousands of novel RNA species across all major RNA biotypes, including a hitherto poorly-cataloged class of non-polyadenylated single-exon long non-coding RNAs. In addition, we exploit intron abundance estimates from total RNA-sequencing to test and verify functional regulation by novel non-coding RNAs. Our study represents a substantial expansion of the current catalogue of human ncRNAs and their regulatory interactions. All data, analyses, and results are available in the R2 web portal and serve as a basis to further explore RNA biology and function.
(p)ppGpp directly regulates translation initiation during entry into quiescence
Authors: Diez Simon , Ryu Jaewook , Caban Kelvin , Gonzalez Ruben L. , Dworkin Jonathan
Published: October 2019

Many bacteria exist in a state of metabolic quiescence where they must minimize energy consumption so as to maximize available resources over a potentially extended period of time. As protein synthesis is the most energy intensive metabolic process in a bacterial cell, it would be an appropriate target for downregulation during the transition from growth to quiescence. We find that whenBacillus subtilisexits growth, a subpopulation of cells emerges with very low levels of protein synthesis dependent on synthesis of the nucleotides (p)ppGpp. We show that (p)ppGpp inhibits protein synthesisin vivoandin vitroby preventing the allosteric activation of the essential GTPase Initiation Factor 2 (IF2) during translation initiation. Finally, we demonstrate that IF2 is an authenticin vivotarget of (p)ppGpp during the entry into quiescence, thus providing a mechanistic basis for the observed attenuation of protein synthesis.
Cell-type-specific dysregulation of RNA alternative splicing in short tandem repeat mouse knockin models of myotonic dystrophy
Authors: Nutter Curtis A. , Bubenik Jodi L. , Oliveira Ruan , Ivankovic Franjo , Sznajder Łukasz J. , Kidd Benjamin M. , Pinto Belinda S. , Otero Brittney A. , Carter Helmut A. , Vitriol Eric A. , Wang Eric T. , Swanson Maurice S.
Published: October 2019

Short tandem repeats (STRs) are prone to expansion mutations that cause multiple hereditary neurological and neuromuscular diseases. To study pathomechanisms using mouse models that recapitulate the tissue specificity and developmental timing of an STR expansion gene, we used rolling circle amplification and CRISPR/Cas9-mediated genome editing to generate Dmpk CTG expansion (CTGexp) knockin models of myotonic dystrophy type 1 (DM1). We demonstrate that skeletal muscle myoblasts and brain choroid plexus epithelial cells are particularly susceptible to Dmpk CTGexp mutations and RNA missplicing. Our results implicate dysregulation of muscle regeneration and cerebrospinal fluid homeostasis as early pathogenic events in DM1.
Biallelic loss of GNAS in a patient with pediatric medulloblastoma
Authors: Tokita Mari J. , Nahas Shareef , Briggs Benjamin , Malicki Denise M. , Mesirov Jill P. , Reyes Iris Anne C. , Farnaes Lauge , Levy Michael L. , Kingsmore Stephen F. , Dimmock David , Crawford John R. , Wechsler-Reya Robert J.
Published: October 2019

Genome sequencing was performed on matched normal and tumor tissue from a 6.5-yr-old boy with a diagnosis of recurrent medulloblastoma. A pathogenic heterozygous c.432+1G>A canonical splice donor site variant in GNAS was detected on analysis of blood DNA. Analysis of tumor DNA showed the same splice variant along with copy-neutral loss of heterozygosity on Chromosome 20 encompassing GNAS, consistent with predicted biallelic loss of GNAS in the tumor specimen. This case strengthens the evidence implicating GNAS as a tumor-suppressor gene in medulloblastoma and highlights a scenario in which therapeutics targeting the cAMP pathway may be of great utility.
High-viscosity sample-injection device for serial femtosecond crystallography at atmospheric pressure
Authors: Shimazu Yoshiaki , Tono Kensuke , Tanaka Tomoyuki , Yamanaka Yasuaki , Nakane Takanori , Mori Chihiro , Terakado Kimura Kanako , Fujiwara Takaaki , Sugahara Michihiro , Tanaka Rie , Doak R. Bruce , Shimamura Tatsuro , Iwata So , Nango Eriko , Yabashi Makina
Published: October 2019

A sample-injection device has been developed at SPring-8 Angstrom Compact Free-Electron Laser (SACLA) for serial femtosecond crystallography (SFX) at atmospheric pressure. Microcrystals embedded in a highly viscous carrier are stably delivered from a capillary nozzle with the aid of a coaxial gas flow and a suction device. The cartridge-type sample reservoir is easily replaceable and facilitates sample reloading or exchange. The reservoir is positioned in a cooling jacket with a temperature-regulated water flow, which is useful to prevent drastic changes in the sample temperature during data collection. This work demonstrates that the injector successfully worked in SFX of the human A2A adenosine receptor complexed with an antagonist, ZM241385, in lipidic cubic phase and for hen egg-white lysozyme microcrystals in a grease carrier. The injection device has also been applied to many kinds of proteins, not only for static structural analyses but also for dynamics studies using pump–probe techniques.
The role of reciprocity in the internationalization of social enterprises
Authors: Evans Klavdia Markelova , Ermilina Veronika , Salaiz Ashley
Published: October 2019

Purpose

The paper enhances our understanding of how small businesses with a strong social mission undergo international expansion. Building on the theoretical arguments on social exchange theory (SET), specifically on the literature on reciprocity, the purpose of this paper is to investigate the applicability of the Uppsala Internationalization Model to the context of a social enterprise (SE). The propositions argue that the strong social orientation of SEs encourages a reciprocal exchange with the stakeholders of the host country that limits the number of obstacles they may face during the internationalizing process.

Design/methodology/approach

The conceptual development bridges SET with bodies of knowledge on SE, Uppsala Internationalization Model and organizational embeddedness.

Findings

The theoretical arguments provide evidence of how the socially oriented mission of a small business aids it with overcoming obstacles presented by internationalization. Specifically, the authors show that socially oriented enterprises are uniquely equipped to conquer the lack of adequate information about a foreign market and a lack of adequate public support in a host country. A social mission, which ignites positive reciprocity with the local stakeholders, serves as a valuable asset in the process of internationalization. Moreover, since the propositions recognize that the norms of reciprocity differ from one national culture to another, they unfold how reciprocal exchanges may be altered because of the nuances of national culture.

Originality/value

This work makes three important contributions. First, it extends our understanding of why SEs can potentially internationalize more rapidly than organizations without a strongly pronounced social mission. Second, the investigation on the applicability of the U-Model to the context of SE answers scholars’ recent call for continuous work on advancing the U-Model. Third, the authors equip practitioners with a thorough understanding of how they can capitalize on the social aspect of a SE in the unique setting of a specific national culture.
An assessment of forerunners for customer loyalty in the selected financial sector by SEM approach toward their effect on business
Authors: Das Subhankar , Nayyar Anand , Singh Inderpal
Published: October 2019

Purpose

The purpose of this paper is to identify and describe the relationship between the precursors and consequences of customer loyalty (CL) in the Indian financial sector, specially banking and insurance context, taking a sample of individual customers as respondents from the Indian State of Punjab.

Design/methodology/approach

The collected data have been analyzed using univariate, bivariate and multivariate analysis techniques. Specifically, descriptive statistics have been assessed to examine the basic characteristics of the sample data. Confirmatory factor analysis with maximum likelihood criteria has been adopted for the measurement and validation of various constructs. Independent samples t-test has been used to compare the CL of public and private firms, banks and insurance firms, and for some of the demographic variables like gender, marital status, etc. One-way ANOVA has been used to compare the CL for variables having more than two groups. Structural equation modeling (SEM) has been used to measure the impact of CL on the BP of financial services firms.

Findings

The result shows that BP is a higher-order construct measured in terms of word-of-mouth, repurchase intention, price premium and share of wallet. Though each of the four measures of CL is special and unique in nature, yet a high level of positive correlation has been seen among these dimensions. The study reveals that CL is not significantly different for the banking firms and insurance firms in Punjab.

Research limitations/implications

The authors consider this work as one of the foundational elements that will enable further advances toward the governance of multi-layer business impact modeling systems. Extensive usability tests would enable to further confirm the findings of the paper. This study contributes to the customer relationship management and services marketing literature by providing empirical support for CL and BP relationship in the Indian context.

Practical implications

The approach described here should improve the maintainability, reuse and clarity of business process models and in extension improve data for CL in large banking and insurance organizations. The approaches described here should improve the maintainability, reuse and clarity of loyalty and relationship of the customer with that of organizations. This can improve data for customer relationship and loyalty in banking and insurance sector.

Originality/value

This paper fulfills an identified gap to enabling SEM enabled models for data regarding customer relationship and loyalty. Loyalty revolves around the concept of relationship. CL is not a new concept, but recent years have demonstrated a developing interest to fabricate CL because of customer-oriented techniques or strategies. Over the previous era, CL has been broadly inspected inside marketing, trades and transactions. It can be concluded that the CL significantly influences BP.
Work–life balance for native and migrant scholars in German academia: meanings and practices
Authors: Gewinner Irina
Published: October 2019

Purpose

The purpose of this paper is to address notions and practices relating to work–life balance for native German scholars and researchers who have migrated from the former Soviet Union (FSU). Issues will be explored from a cultural perspective, identifying culturally based interpretations of work–life balance.

Design/methodology/approach

Foregrounded in a diversity approach, this empirical study draws upon explorative interviews to discuss work–life balance in German academia. To overcome monocultural observations, 25 German scholars and 11 researchers originating from the FSU were interviewed, all of whom are highly skilled female scholars.

Findings

Findings demonstrate that individuals with diverse cultural backgrounds can perceive huge differences in identical working conditions. The study links meanings of work–life balance with individual practices and identifies key components of work–life balance within this population. It also discusses the decisions that scholars make about starting families or remaining childless for the sake of their careers.

Originality/value

This study is the first of its kind in Germany, and represents a strong implication for policies and their evaluation. It identifies the crucial role played by culturally rooted notions relating to work–life balance practices.
Numerical study of the effects of ventilated cavities outlet location on thermal comfort and air quality
Authors: Younsi Zohir , Koufi Lounes , Naji Hassane
Published: October 2019

Purpose

A comprehensive investigation on the outlet air position effects on the thermal comfort and air quality has been achieved. In addition, airflow and temperature distributions in ventilated cavities filled with an air-CO2 mixture with mixed convection are predicted. The airflow enters from the cavity through an opening in the lower side of the left vertical wall and exits through the opening in one wall of the cavity. This paper aims to investigate the outlet location effect, four different placement configurations of output ports are considered. Three of them are placed on the upper side and the fourth on top of the opposite side of the inlet opening. A uniform heat and CO2 contaminant source are applied on the left vertical wall, while the remaining walls are impermeable and adiabatic to heat and solute. The cooling efficiency inside the enclosure and the average fluid temperature are computed for different Reynolds and Rayleigh numbers to find the most suitable fluid outlet position that ensures indoor comfortable conditions while effectively removing heat and the contaminant. This is demonstrated by three relevant indices, namely, the effectiveness for heat removal, the contaminant removal and the index of indoor air quality.

Design/methodology/approach

The simulations were performed via the finite-volume scSTREAM CFD solver V11. Three different values of CO2 amount are considered, namely, 103, 2 × 103 and 3 × 103 ppm, the Reynolds number being in the range 100 ≤ Re ≤ 800.

Findings

Based on the findings obtained, it is the configuration whose air outlet is placed near the heat source and the contaminant, which provides a better air distribution and a ventilation efficiency compared to the others ventilation strategies.

Originality/value

The studies on heat and mass transfers by natural and forced convection in ventilated cavities remain a fruitful research topic. Thereby, such a study deals with different ventilation strategies through cavities containing an air-CO2 mixture subjected to a mixed regime. In particular, the air inlet velocity and contaminant sources’ effects on thermal comfort and air quality have been investigated.
Do female and independent directors explain the two-way relationship between corporate social responsibility and earnings management of Chinese listed firms?
Authors: Sial Muhammad Safdar , Chunmei Zheng , Khuong Nguyen Vinh
Published: October 2019

Purpose

This study aims to explore the possibility of a two-way relationship between corporate social responsibility (CSR) and earnings management (accruals and real EM) with the moderating role of female and independent directors.

Design/methodology/approach

The authors use STATA to test the generalized method of moments on a sample of Chinese listed ﬁrms data over the period 2009-2015. The unbalanced sample obtained 3,481 observations from China stock market and accounting research database and CSR rating provided by Rankins.

Findings

The results indicate a significant negative relationship between two-way CSR and accrual-based EM. Moreover, female and independent directors moderate the two-way relationship between CSR and EM.

Research limitations/implications

The present study does not include all financial, insurance and investment firms to impact on CSR and EM. Further research might consist of family ownership to enhance the evidence for an emerging market.

Originality/value

This study primarily contributes to the literature on CSR, female and independent directors, and EM by providing evidence for the moderating role of female and independent directors on the two-way association between CSR and EM.