bluuebunny/crossref_metadata_2025 huggingface dataset:
The circadian clock protein REVERBα inhibits pulmonary fibrosis development
Authors: Cunningham Peter S. , Meijer Peter , Nazgiewicz Alicja , Anderson Simon G. , Borthwick Lee A. , Bagnall James , Kitchen Gareth B. , Lodyga Monika , Begley Nicola , Venkateswaran Rajamayier V. , Shah Rajesh , Mercer Paul F. , Durrington Hannah J. , Henderson Neil C. , Piper-Hanley Karen , Fisher Andrew J. , Chambers Rachel C. , Bechtold David A. , Gibbs Julie E. , Loudon Andrew S. , Rutter Martin K. , Hinz Boris , Ray David W. , Blaikley John F.
Published: September 2019

Pulmonary inflammatory responses lie under circadian control; however the importance of circadian mechanisms in fibrosis is not understood. Here, we identify a striking change to these mechanisms resulting in a gain of amplitude and lack of synchrony within pulmonary fibrotic tissue. These changes result from an infiltration of mesenchymal cells, an important cell type in the pathogenesis of pulmonary fibrosis. Mutation of the core clock protein REVERBα in these cells exacerbated the development of bleomycin-induced fibrosis, whereas mutation of REVERBα in club or myeloid cells had no effect on the bleomycin phenotype. Knockdown of REVERBα revealed regulation of the poorly described transcription factor TBPL1. Both REVERBα and TBPL1 altered integrinβ1 focal adhesion formation, resulting in increased myofibroblast activation. The translational importance of our findings was established through analysis of two human cohorts. In the UK Biobank circadian strain markers (sleep length, chronotype and shift work) are associated with pulmonary fibrosis making them novel risk factors. In a separate cohort REVERBα expression was increased in human idiopathic pulmonary fibrosis (IPF) lung tissue. Pharmacological targeting of REVERBα inhibited myofibroblast activation in IPF fibroblasts and collagen secretion in organotypic cultures from IPF patients, suggesting targeting REVERBα could be a viable therapeutic approach.

Significance

The circadian clock plays an essential role in energy metabolism, and inflammation. In contrast the importance of the clock in the pathogenesis of fibrosis remains poorly explored. This study describes a striking alteration in circadian biology during pulmonary fibrosis where the relatively arrhythmic alveolar structures gain circadian but desynchronous rhythmicity due to infiltration by fibroblasts. Disruption of the clock in these cells, which are not widely implicated in circadian pathophysiology, results in a pro-fibrotic phenotype. Translation of these findings in humans revealed previously unrecognised important circadian risk factors for pulmonary fibrosis (sleep length, chronotype and shift work). In addition, targeting REVERBα repressed collagen secretion from human fibrotic lung tissue making this protein a promising therapeutic target.
Optimizing auditory brainstem response acquisition using interleaved frequencies
Authors: Buran Brad N. , Elkins Sean , Kempton J. Beth , Porsov Edward V. , Brigande John V. , David Stephen V.
Published: September 2019

Auditory brainstem responses (ABRs) require averaging responses to hundreds or thousands of repetitions of a stimulus (e.g., tone pip) to obtain a measurable evoked response at the scalp. Fast repetition rates lead to changes in ABR amplitude and latency due to adaptation. To minimize the effect of adaptation, stimulus rates are sometimes as low as 10 to 13.3 stimuli per second, requiring long acquisition times. The trade-off between reducing acquisition time and minimizing the effect of adaptation on ABR responses is an especially important consideration for studies of cochlear synaptopathy, which use the amplitude of short latency responses (wave 1) to assess auditory nerve survival. It has been proposed that adaptation during ABR acquisition can be reduced by interleaving tones at different frequencies, rather than testing each frequency serially. With careful ordering of frequencies and levels in the stimulus train, adaptation in the auditory nerve can be minimized, thereby permitting an increase in the rate at which tone bursts are presented. However, widespread adoption of this stimulus design has been hindered by lack of available software. Here, we develop and validate an interleaved stimulus design to optimize the rate of ABR measurement while minimizing adaptation. We implement this method in an open-source data acquisition software tool that permits either serial or interleaved ABR measurements. The open-source software library, psiexperiment, is compatible with widely-used ABR hardware. Consistent with previous studies, careful design of an interleaved stimulus train can reduce ABR acquisition time by more than half, with minimal effect on ABR thresholds and wave 1 latency, while improving measures of wave 1 amplitude.
A dopamine-induced gene expression signature regulates neuronal function and cocaine response
Authors: Savell Katherine E. , Zipperly Morgan E. , Tuscher Jennifer J. , Duke Corey G. , Phillips Robert A. , Bauman Allison J. , Thukral Saakshi , Sultan Faraz A. , Goska Nicholas A. , Ianov Lara , Day Jeremy J.
Published: September 2019

Drug addiction is a worldwide health problem, with overdose rates of both psychostimulants and opioids currently on the rise in many developed countries. Drugs of abuse elevate dopamine levels in the nucleus accumbens (NAc) and alter transcriptional programs believed to promote long-lasting synaptic and behavioral adaptations. However, even with well-studied drugs such as cocaine, drug-induced transcriptional responses remain poorly understood due to the cellular heterogeneity of the NAc and complex drug actions via multiple neurotransmitter systems. Here, we leveraged high-throughput single-nucleus RNA-sequencing to create a comprehensive molecular atlas of cell subtypes in the NAc, defining both sex-specific and cell type-specific responses to acute cocaine experience in a rat model system. Using this transcriptional map, we identified specific neuronal subpopulations that are activated by cocaine, and defined an immediate early gene expression program that is upregulated following cocaine experiencein vivoand dopamine (DA) receptor activationin vitro. To characterize the neuronal response to this DA-mediated gene expression signature, we engineered a large-scale CRISPR/dCas9 activation strategy to recreate this program. Multiplexed induction of this gene program initiated a secondary synapse-centric transcriptional profile, altered striatal physiologyin vitro, and enhanced cocaine sensitizationin vivo. Taken together, these results define the genome-wide transcriptional response to cocaine with cellular precision, and demonstrate that drug-responsive gene programs are sufficient to initiate both physiological and behavioral adaptations to drugs of abuse.
Dissectingpsalocus regulation inYersinia pestis
Authors: Li Peng , Wang Xiuran , Smith Carol , Shi Yixin , Wade Joseph T , Sun Wei
Published: September 2019

The pH 6 antigen ofYersinia pestisis a virulence factor that is expressed in response to high temperature (37 °C) and low pH (6.0). Previous studies have implicated the PsaE and PsaF regulators in the temperature- and pH-dependent regulation ofpsaA. Here, we show that PsaE levels are themselves controlled by pH and temperature, explaining the regulation ofpsaA. We identify hundreds of binding sites for PsaE across theY. pestisgenome, with the majority of binding sites located in intergenic regions. However, we detect direct regulation of very few genes by PsaE, suggesting either that most binding sites are non-regulatory, or that they require additional environmental cues. We also identify the precise binding site for PsaE that is required for temperature- and pH-dependent regulation ofpsaA. Thus, our data reveal the critical function that PsaE plays in regulation ofpsaA, and suggest that PsaE may have many additional regulatory targets.
A conserved expression signature predicts growth rate and reveals cell & lineage-specific differences
Authors: Jiang Zhisheng , Generoso Serena Francesca , Badia Marta , Payer Bernhard , Carey Lucas B.
Published: September 2019

Isogenic cells cultured together show heterogeneity in their proliferation rate. To determine the differences between fast and slow-proliferating cells, we developed a method to sort cells by proliferation rate, and performed RNA-seq on slow and fast proliferating subpopulations of pluripotent mouse embryonic stem cells (mESCs) and mouse fibroblasts. We found that slowly proliferating mESCs have a more naïve pluripotent character. We identified an evolutionarily conserved proliferation-correlated transcriptomic signature that is common to all eukaryotes: fast cells have higher expression of genes for protein synthesis and protein degradation. This signature accurately predicted growth rate in yeast and cancer cells, and identified lineage-specific proliferation dynamics during development, usingC. elegansscRNA-seq data. In contrast, sorting by mitochondria membrane potential revealed a highly cell-type specific mitochondria-state related transcriptome. mESCs with hyperpolarized mitochondria are fast proliferating, while the opposite is true for fibroblasts. The mitochondrial electron transport chain inhibitor antimycin affected slow and fast subpopulations differently. While a major transcriptional-signature associated with cell-to-cell heterogeneity in proliferation is conserved, the metabolic and energetic dependency of cell proliferation is cell-type specific.

Synopsis

By performing RNA-seq on cells FACS sorted by their proliferation rate, this study identifies a gene expression signature capable of predicting proliferation rates in diverse eukaryotic cell types and species. This signature, applied to scRNAseq data fromC.elegans, reveals lineage-specific differences in proliferation during development. In contrast to the universality of the proliferation signature, mitochondria and metabolism related genes show a high degree of cell-type specificity; mouse pluripotent stem cells (mESCs) and differentiated cells (fibroblasts) exhibit opposite relations between mitochondria state and proliferation. Furthermore, we identified a slow proliferating subpopulation of mESCs with higher expression of pluripotency genes. Finally, we show that fast and slow proliferating subpopulations are differentially sensitive to mitochondria inhibitory drugs in different cell types.

Highlights

A FACS-based method to determine the transcriptomes of fast and slow proliferating subpopulations.

A universal proliferation-correlated transcriptional signature indicates high protein synthesis and degradation in fast proliferating cells across cell types and species.

Applied to scRNA-seq, the expression signature predicts correctly the global slowdown in proliferation duringC. elegansdevelopment, with lineage-specific exceptions.

Mitochondria membrane potential predicts proliferation rate in a cell-type specific manner, with ETC complex III inhibitor having distinct effects on the proliferation of fibroblasts vs mESCs.
Local states of chromatin compaction at transcription start sites control transcription levels
Authors: Ishihara Satoru , Sasagawa Yohei , Kameda Takeru , Umeda Mana , Yamashita Hayato , Kotomura Naoe , Abe Masayuki , Shimono Yohei , Nikaido Itoshi
Published: September 2019

A defined amount of transcript is produced from transcription start sites (TSSs) of each gene, suggesting that the binding frequency of RNA polymerase varies among genes. However, what structure in chromatin controls this frequency remains elusive. We established a method to fractionate chromatin according to its degree of three-dimensional compaction. Nucleosomes were evenly detected through all of the fractions, but histone H1 was more highly enriched in the more compact chromatin fractions. Similarly, HP1α and MBD2b were more abundant in more compact chromatin, while the levels of tri-methylated H3 (Lys9) and 5-methyl cytosine subtly increased. Via genome-wide analyses, nearly the entire genome was found to exist in compact chromatin without variations between repeat and non-repeat sequences; however, active TSSs were rarely found in compact chromatin. Based on a correlation between weak compaction and RNA polymerase binding at TSSs, it appears that local states of chromatin compaction determine transcription levels.
GSAlign – an efficient sequence alignment tool for intra-species genomes
Authors: Lin Hsin-Nan , Hsu Wen-Lian
Published: September 2019

Personal genomics and comparative genomics are becoming more important in clinical practice and genome research. Both fields require sequence alignment to discover sequence conservation and variation. Though many methods have been developed, some are designed for small genome comparison while some are not efficient for large genome comparison. Moreover, most existing genome comparison tools have not been evaluated the correctness of sequence alignments systematically. A wrong sequence alignment would produce false sequence variants. In this study, we present GSAlign that handles large genome sequence alignment efficiently and identifies sequence variants from the alignment result. GSAlign is an efficient sequence alignment tool for intra-species genomes. It identifies sequence variations from the sequence alignments. We estimate performance by measuring the correctness of predicted sequence variations. The experiment results demonstrated that GSAlign is not only faster than most existing state-of-the-art methods, but also identifies sequence variants with high accuracy.
Translational efficiency across healthy and tumor tissues is proliferation-related
Authors: Hernandez-Alias Xavier , Benisty Hannah , Schaefer Martin H. , Serrano Luis
Published: September 2019

Background

Different tissues express genes with particular codon usage and anticodon tRNA repertoires. However, the codon-anticodon co-adaptation in humans is not completely understood, as well as its effect on tissue-specific protein levels.

Results

We first validated the accuracy of small RNA-seq for tRNA quantification across five human cell lines. We then analyzed tRNA expression in more than 8000 tumor samples from TCGA, together with their paired mRNA-seq and proteomics data, to determine the Relative Translation Efficiency. We thereby elucidate that the dynamic adaptation of the tRNA pool is largely related to the proliferative state across tissues, which determines tissue-specific translation efficiency. Furthermore, the aberrant translational efficiency of ProCCA and GlyGGT in cancer, among other codons, which is partly regulated by the tRNA gene copy numbers and their promoter DNA methylation, is associated with poor patient survival.

Conclusions

The distribution of tissue-specific tRNA pools over the whole cellular translatome affects the subsequent translational efficiency, which functionally determines a condition-specific expression program in tissues both in healthy and tumor states.
An efficient single-cell transcriptomics workflow to assess protist diversity and lifestyle
Authors: Onsbring Henning , Tice Alexander K. , Barton Brandon T. , Brown Matthew W. , Ettema Thijs J. G.
Published: September 2019

Most diversity in the eukaryotic tree of life are represented by microbial eukaryotes, which is a polyphyletic group also referred to as protists. Among the protists, currently sequenced genomes and transcriptomes give a biased view of the actual diversity. This biased view is partly caused by the scientific community, which has prioritized certain microbes of biomedical and agricultural importance. Additionally, it is challenging to establish protist cultures, which further influence what has been studied. It is now possible to bypass the time-consuming process of cultivation and directly analyze the gene content of single protist cells. Single-cell genomics was used in the first experiments where individual protists cells were genomically explored. Unfortunately, single-cell genomics for protists are often associated with low genome recovery and the assembly process can be complicated because of repetitive intergenic regions. Sequencing repetitive sequences can be avoided if single-cell transcriptomics is used, which only targets the part of the genome that is transcribed. In this study we test different modifications of Smart-seq2, a single-cell RNA sequencing protocol originally developed for mammalian cells, to establish a robust and more cost-efficient workflow for protists. The diplomonad Giardia intestinalis was used in all experiments and the available genome for this species allowed us to benchmark our results. We could observe increased transcript recovery when freeze-thaw cycles were added as an extra step to the Smart-seq2 protocol. Further we tried reducing the reaction volume and purifying with alternative beads to test different cost-reducing changes of Smart-seq2. Neither improved the procedure, and cutting the volumes by half actually led to significantly fewer genes detected. We also added a 5’ biotin modification to our primers and reduced the concentration of oligo-dT, to potentially reduce generation of artifacts. Except adding freeze-thaw cycles and reducing the volume, no other modifications lead to a significant change in gene detection. Therefore, we suggest adding freeze-thaw cycles to Smart-seq2 when working with protists and further consider our other modification described to improve cost and time-efficiency.
Missing-In-Metastasis / Metastasis Suppressor 1 regulates B cell receptor signaling, B cell metabolic potential and T cell-independent immune responses
Authors: Sarapulov Alexey V , Petrov Petar , Hernández-Pérez Sara , Šuštar Vid , Kuokkanen Elina , Vinod Rufus , Vainio Marika , Cords Lena , Fritzsche Marco , Carrasco Yolanda R , Mattila Pieta K
Published: September 2019

Efficient generation of antibodies by B cells is one of the prerequisites of protective immunity. B cell activation by cognate antigens via B cell receptors (BCR), or pathogen-associated molecules through pattern-recognition receptors, such as Toll-like receptors (TLRs), leads to transcriptional and metabolic changes that ultimately transform B cells into antibody producing plasma cells or memory cells. BCR signaling and a number of steps downstream of it rely on coordinated action of cellular membranes and the actin cytoskeleton, tightly controlled by concerted action of multiple regulatory proteins, some of them exclusive to B cells. Here, we dissect the role of Missing-In-Metastasis (MIM), or Metastasis suppressor 1 (MTSS1), a cancer-associated membrane and actin cytoskeleton regulating protein, in B cell-mediated immunity by taking advantage of MIM knockout mouse strain. We show undisturbed B cell development and largely normal composition of B cell compartments in the periphery. Interestingly, we found that MIM−/−B cells are defected in BCR signaling in response to surface-bound antigens but, on the other hand, show increased metabolic activity after stimulation with LPS or CpG.In vivo, MIM knockout animals exhibit impaired IgM antibody responses to immunization with T cell-independent antigen. This study provides the first comprehensive characterization of MIM in B cells, demonstrates its regulatory role for B cell-mediated immunity, as well as proposes new functions for MIM in tuning receptor signaling and cellular metabolism, processes which may also contribute to the poorly understood functions of MIM in cancer.
MSqRob takes the missing hurdle: uniting intensity- and count-based proteomics
Authors: Goeminne Ludger J.E. , Sticker Adriaan , Martens Lennart , Gevaert Kris , Clement Lieven
Published: September 2019

Missing values are a major issue in quantitative data-dependent mass spectrometry-based proteomics. We therefore present an innovative solution to this key issue by introducing a hurdle model, which is a mixture between a binomial peptide count and a peptide intensity-based model component. It enables dramatically enhanced quantification of proteins with many missing values without having to resort to harmful assumptions for missingness. We demonstrate the superior performance of our method by comparing it with state-of-the-art methods in the field.
Two-dimensional NMR lineshape analysis of single, multiple, zero and double quantum correlation experiments
Authors: Waudby Christopher A. , Ouvry Margaux , Davis Ben , Christodoulou John
Published: September 2019

NMR spectroscopy provides a powerful approach for the characterisation of chemical exchange and molecular interactions by analysis of series of experiments acquired over the course of a titration measurement. The appearance of NMR resonances undergoing chemical exchange depends on the frequency difference relative to the rate of exchange, and in the case of one-dimensional experiments chemical exchange regimes are well established and well known. However, two-dimensional experiments present additional complexity, as at least one additional frequency difference must be considered. Here we provide a systematic classification of chemical exchange regimes in two-dimensional NMR spectra. We highlight important differences between exchange in HSQC and HMQC experiments, that on a practical level result in more severe exchange broadening in HMQC spectra, but show that complementary alternatives to the HMQC are available in the form of HZQC and HDQC experiments. We present the longitudinal relaxation optimised SOFAST-H(Z/D)QC experiment for the simultaneous acquisition of sensitivity-enhanced HZQC and HDQC spectra, and the longitudinal and transverse relaxation optimised BEST-ZQ-TROSY for analysis of large molecular weight systems. We describe the application of these experiments to the characterisation of the interaction between the Hsp90 N-terminal domain and a small molecule ligand, and show that the independent analysis of HSQC, HMQC, HZQC and HDQC experiments provides improved confidence in the fitted dissociation constant and dissociation rate. Joint analysis of such data may provide improved sensitivity to detect and analyse more complex multi-state interaction mechanisms such as induced fit or conformational selection.
Exploration of insulin amyloid polymorphism using Raman spectroscopy and imaging
Authors: Ishigaki M. , Morimoto K. , Chatani E. , Ozaki Y.
Published: September 2019

We aimed to investigate insulin amyloid fibril polymorphism caused by salt effects and heating temperature, and to visualize the structural differences of the polymorphismsin situusing Raman imaging without labeling. The time course monitoring for amyloid formation was carried out in an acidic condition without any salts and with two species of salts (NaCl and Na2SO4) by heating at 60, 70, 80, and 90 ℃. The intensity ratio of two Raman bands at 1672 and 1657 cm-1due to β-sheet and α-helix structures was revealed to be an indicator of amyloid fibril formation, and the relative proportion of the β-sheet structure was higher in the case with salts, especially at a higher temperature and with Na2SO4. In conjunction with the secondary structural changes of proteins, the S-S stretching vibrational mode of a disulfide bond (∼514 cm-1) and the ratio of the tyrosine doubletR(I850⁄I826) were also found to be markers distinguishing polymorphisms of insulin amyloid fibrils by principal component analysis (PCA). Especially, amyloid fibrils with Na2SO4media formed the g-g-g conformation of disulfide bond at a higher rate and without any salts; on the contrary, the g-g-g conformation was partially transformed into the g-g-t conformation at higher temperatures. The different environments of the hydroxyl groups of the tyrosine residue were assumed to be caused by fibril polymorphism. Raman imaging using these marker bands also successfully visualized the two- and three-dimensional structural differences of amyloid polymorphisms. The present results indicate the potential of Raman imaging as a diagnostic tool for polymorphisms in tissues of amyloid-related diseases.

Statement of Significance

Our results revealed three Raman markers distinguishing amyloid fibril polymorphisms caused by salt and temperature effects; the relative proportion of protein secondary structures (α–helix and β-sheet), the ratio of tyrosine doublet, and the conformational differences of disulfide bonds. The lower values of tyrosine doublet in the case with salts were interpreted as the anions rob the hydration water from proteins which induced protein misfolding. Using these parameters, Raman images captured their higher order structural differencesin situwithout labeling. The images of hydrogen bonds strength variations due to tyrosine doublet is believed to include significant novelty. The present results imply the potential of Raman imaging for use as a diagnostic imaging tool for tissues with amyloid-induced diseases.
Blue light-induced gene expression alterations in cultured neurons are the result of phototoxic interactions with neuronal culture media
Authors: Duke Corey G. , Savell Katherine E. , Phillips Robert A. , Day Jeremy J.
Published: September 2019

Blue waveform light is used as an optical actuator in numerous optogenetic technologies employed in neuronal systems. However, the potential side effects of blue waveform light in neurons has not been thoroughly explored, and recent reports suggest that neuronal exposure to blue light can induce transcriptional alterations in vitro and in vivo. Here, we examined the effects of blue waveform light in cultured primary rat cortical neurons. Exposure to blue light (470nm) resulted in upregulation of several immediate early genes (IEGs) traditionally used as markers of neuronal activity, including Fos and Fosb, but did not alter the expression of circadian clock genes Bmal1, Cry1, Cry2, Clock, or Per2. IEG expression was increased following 4 hours of 5% duty cycle light exposure, and IEG induction was not dependent on light pulse width. Elevated levels of blue light exposure induced a loss of cell viability in vitro, suggestive of overt phototoxicity. Changes in gene expression induced by blue waveform light were prevented when neurons were cultured in a photoinert media supplemented with a photostable neuronal supplement instead of commonly utilized neuronal culture media and supplements. Together, these findings suggest that light-induced gene expression alterations observed in vitro stem from a phototoxic interaction between commonly used media and neurons, and offer a solution to prevent this toxicity when using photoactivatable technology in vitro.
A High-Resolution Landscape of Mutations in the BCL6 Super-Enhancer in Normal Human B-Cells
Authors: Shen Jiang-Cheng , Kamath-Loeb Ashwini S. , Kohrn Brendan F. , Loeb Keith R. , Preston Bradley D. , Loeb Lawrence A.
Published: September 2019

The super-enhancers (SE) of lineage-specific genes in B-cells are off-target sites of somatic hypermutation. However, the inability to detect sufficient numbers of mutations in normal human B-cells has precluded the generation of a high-resolution mutational landscape of SEs. Here, we captured and sequenced 12 B-cell SEs at single-nucleotide resolution from ten healthy individuals across diverse ethnicities. We detected a total of ∼9000 subclonal mutations (allele frequencies <0.1%); of these, ∼8000 are present in the BCL6 SE alone. Within the BCL6 SE, we identified three regions of clustered mutations where the mutation frequency is ∼7X10-4. Mutational spectra show a predominance of C>T/G>A and A>G/T>C substitutions, consistent with the activities of activation-induced-cytidine deaminase (AID) and the A-T mutator, DNA Polymerase η, respectively, in mutagenesis in normal B-cells. Analyses of mutational signatures further corroborate the participation of these factors in this process. Single base substitution signature SBS85, SBS37, and SBS39 were found in the BCL6 SE. While SBS85 is a denoted signature of AID in lymphoid cells, the etiologies of SBS37 and SBS39 are still unknown. Our analysis suggests the contribution of error-prone DNA polymerases to the latter signatures. The high-resolution mutation landscape has enabled accurate profiling of subclonal mutations in B-cell SEs in normal individuals. By virtue of the fact that subclonal SE mutations are clonally expanded in B-cell lymphomas, our studies also offer the potential for early detection of neoplastic alterations.

Significance

We used Duplex Sequencing to detect low-frequency mutations in the BCL6 super-enhancer locus in normal human B-cells. The landscape of pre-existing mutations is remarkably conserved across different ethnicities and reveals clustered mutational hotspots that correlate with reported sites of clonal mutations and translocation breakpoints in human B-cell lymphomas. This high-resolution genomic landscape revealed by Duplex Sequencing offers accurate and thorough profiling of low frequency, pre-existing mutations in normal individuals, and the potential for early detection of neoplastic alterations.
Local adaptation to abiotic and biotic stresses and phenotypic selection on flowering time in annual Brachypodium spp. along an aridity gradient
Authors: Penner Shira , Sapir Yuval
Published: September 2019

Plants have diverse strategies to cope with stress, including early flowering to “escape” abiotic stress and late flowering to mitigate biotic stress. Plants are usually exposed to multiple stresses simultaneously, but little is known about the impact of multiple co-occurring stresses on plant evolution.

We tested for adaptation to both aridity and interspecific competition of the model plant Brachypodium spp., collected along the aridity gradient in Israel. We recorded flowering time and estimated fitness in a controlled watering experiment, with treatments mimicking Mediterranean and arid precipitation, and in two common gardens located in the extremes of the gradient (i.e., desert and mesic Mediterranean). At the latter we also manipulated interspecific competition to examine the combined effect of competition and aridity.

Plants from arid environments always flowered earlier, but we found no selection on flowering time in the watering experiment. In the common gardens, however, the direction of selection on flowering time differed between sites and competition treatments.

We conclude that interactions between aridity and competition drive local adaptation of Brachypodium in the Eastern Mediterranean basin. Variation in flowering time is an important adaptive mechanism to aridity and multiple selection agents can have interactive effects on the evolution of this trait.
Structural rearrangements drive extensive genome divergence between symbiotic and free-living Symbiodinium
Authors: González-Pech Raúl A. , Stephens Timothy G. , Chen Yibi , Mohamed Amin R. , Cheng Yuanyuan , Burt David W. , Bhattacharya Debashish , Ragan Mark A. , Chan Cheong Xin
Published: September 2019

Symbiodiniaceae are predominantly symbiotic dinoflagellates critical to corals and other reef organisms. Symbiodinium is a basal symbiodiniacean lineage and includes symbiotic and free-living taxa. However, the molecular mechanisms underpinning these distinct lifestyles remain little known. Here, we present high-quality de novo genome assemblies for the symbiotic Symbiodinium tridacnidorum CCMP2592 (genome size 1.3 Gbp) and the free-living Symbiodinium natans CCMP2548 (genome size 0.74 Gbp). These genomes display extensive sequence divergence, sharing only ~1.5% conserved regions (≥90% identity). We predicted 45,474 and 35,270 genes for S. tridacnidorum and S. natans, respectively; of the 58,541 homologous gene families, 28.5% are common to both genomes. We recovered a greater extent of gene duplication and higher abundance of repeats, transposable elements and pseudogenes in the genome of S. tridacnidorum than in that of S. natans. These findings demonstrate that genome structural rearrangements are pertinent to distinct lifestyles in Symbiodinium, and may contribute to the vast genetic diversity within the genus, and more broadly in Symbiodiniaceae. Moreover, the results from our whole-genome comparisons against a free-living outgroup support the notion that the symbiotic lifestyle is a derived trait in, and that the free-living lifestyle is ancestral to, Symbiodinium.
Age-related changes in human emotional egocentricity: evidence from multi-level neuroimaging
Authors: Riva Federica , Lenger Melanie , Kronbichler Martin , Lamm Claus , Silani Giorgia
Published: September 2019

Emotional egocentric bias (EEB) occurs when, due to a partial failure in self-other distinction, empathy for another’s emotions is influenced by our own emotional state. Recent studies have demonstrated that this bias is higher in children, adolescents and older adults than in young adults. In the latter, overcoming emotional egocentrism has been associated with significant activity in the right supramarginal gyrus (rSMG), as well as increased connectivity between rSGM and somatosensory and visual cortices. Investigations on the neural correlates of EEB in adolescents and older adults are missing. We filled this gap, by asking female participants from three different age groups (adolescents, young adults and older adults, N=92) to perform a well-validated EEB task (Silani et al., 2013) in an MRI scanner. A multi-level analysis approach of MRI data including functional segregation, effective connectivity and structural analyses was adopted. Results revealed higher EEB in older compared to young adults and a comparable EEB in adolescents and young adults. Age-related differences in EEB were associated with differences in task-related rSMG connectivity with somatosensory cortices, especially with S2, which acted as a partial mediator between age and EEB. These findings provide further evidence for the crucial role of the rSMG in self-other distinction in the emotional domain, and suggest that the age-related decline in overcoming EEB is best explained by changes in rSMG connectivity rather than decreased regional activity in that area. This advocates a more systematic investigation of task-related connectivity in studies on aging and life-span development of social-cognitive phenomena.

Significance Statement

Empathy comprises both the ability to identify and share another’s emotional state, and the ability to disentangle one’s own from the other’s emotional state. When self- and other-related emotions are conflicting, empathy might be negatively influenced by egocentric tendencies. This phenomenon is referred to as emotional egocentric bias (EEB), with previous research showing that its extent changes across the life-span. Here, we provide evidence that age-related differences in EEB are mainly associated with age-related changes in rSMG effective connectivity, and in particular that higher EEB in older adults is associated to lower rSMG effective connectivity with somatosensory cortices. These findings suggest the importance, particularly in aging, of intact functional connectivity for optimal socio-cognitive functioning.
SRSF2 regulation of MDM2 reveals splicing as a therapeutic vulnerability of the p53 pathway
Authors: Comiskey Daniel F. , Montes Matías , Khurshid Safiya , Singh Ravi K. , Chandler Dawn S.
Published: September 2019

MDM2 is an oncogene and critical negative regulator of tumor suppressor p53. Genotoxic stress causes alternative splicing of MDM2 transcripts, which leads to alterations in p53 activity and contributes to tumorigenesis. MDM2-ALT1 is one of transcripts predominantly produced in response to genotoxic stress and is comprised of terminal coding exons 3 and 12. Previously, we found that SRSF1 induces MDM2-ALT1 by promoting MDM2 exon 11 skipping. Here we report that splicing regulator SRSF2 antagonizes the regulation of SRSF1 by facilitating the inclusion of exon 11 through binding at two conserved exonic splicing enhancers. Overexpression of SRSF2 reduced the generation of MDM2-ALT1 in genotoxic stress condition, whereas knockdown induces the expression of MDM2-ALT1 in absence of genotoxic stress. Consistently, blocking the exon 11 SRSF2 binding sites using oligonucleotides promotes MDM2-ALT1. The regulation of MDM2 splicing by SRSF2 is also conserved in mouse as mutation of one SRSF2 binding site in Mdm2 exon 11, using CRISPR-Cas9, increases the expression MDM2-ALT1 homolog Mdm2-MS2 and proliferation of NIH 3T3 cells. Taken together, these findings underscore the relevance of MDM2 alternative splicing in cancer and suggest that p53 levels can be modulated by artificially regulating MDM2 splicing.
A prioritized planning algorithm of trajectory coordination based on time windows for multiple AGVs with delay disturbance
Authors: Tai Ruochen , Wang Jingchuan , Chen Weidong
Published: September 2019

Purpose

In the running of multiple automated guided vehicles (AGVs) in warehouses, delay problems in motions happen unavoidably as there might exist some disabled components of robots, the instability of networks and the interference of people walking. Under this case, robots would not follow the designed paths and the coupled relationship between temporal and space domain for paths is broken. And there is no doubt that other robots are disturbed by the ones where delays happen. Finally, this brings about chaos or even breakdown of the whole system. Therefore, taking the delay disturbance into consideration in the path planning of multiple robots is an issue worthy of attention and research.

Design/methodology/approach

This paper proposes a prioritized path planning algorithm based on time windows to solve the delay problems of multiple AGVs. The architecture is a unity consisting of three components which are focused on scheduling AGVs under normal operations, delays of AGVs, and recovery of AGVs. In the components of scheduling AGVs under normal operations and recovery, this paper adopts a dynamic routing method based on time windows to ensure the coordination of multiple AGVs and efficient completion of tasks. In the component for scheduling AGVs under delays, a dynamical prioritized local path planning algorithm based on time windows is designed to solve delay problems. The introduced planning principle of time windows would enable the algorithm to plan new solutions of trajectories for multiple AGVs, which could lower the makespan. At the same time, the real-time performance is acceptable based on the planning principle which stipulates the parameters of local time windows to ensure that the computation of the designed algorithm would not be too large.

Findings

The simulation results demonstrate that the proposed algorithm is more efficient than the state-of-the-art method based on homotopy classes, which aims at solving the delay problems. What is more, it is validated that the proposed algorithm can achieve the acceptable real-time performance for the scheduling in warehousing applications.

Originality/value

By introducing the planning principle and generating delay space and local adjustable paths, the proposed algorithm in this paper can not only solve the delay problems in real time, but also lower the makespan compared with the previous method. The designed algorithm guarantees the scheduling of multiple AGVs with delay disturbance and enhances the robustness of the scheduling algorithm in multi-AGV system.
ACD3GPSO: automatic clustering-based algorithm for multi-robot task allocation using dynamic distributed double-guided particle swarm optimization
Authors: Ayari Asma , Bouamama Sadok
Published: September 2019

Purpose

The multi-robot task allocation (MRTA) problem is a challenging issue in the robotics area with plentiful practical applications. Expanding the number of tasks and robots increases the size of the state space significantly and influences the performance of the MRTA. As this process requires high computational time, this paper aims to describe a technique that minimizes the size of the explored state space, by partitioning the tasks into clusters. In this paper, the authors address the problem of MRTA by putting forward a new automatic clustering algorithm of the robots' tasks based on a dynamic-distributed double-guided particle swarm optimization, namely, ACD3GPSO.

Design/methodology/approach

This approach is made out of two phases: phase I groups the tasks into clusters using the ACD3GPSO algorithm and phase II allocates the robots to the clusters. Four factors are introduced in ACD3GPSO for better results. First, ACD3GPSO uses the k-means algorithm as a means to improve the initial generation of particles. The second factor is the distribution using the multi-agent approach to reduce the run time. The third one is the diversification introduced by two local optimum detectors LODpBest and LODgBest. The last one is based on the concept of templates and guidance probability Pguid.

Findings

Computational experiments were carried out to prove the effectiveness of this approach. It is compared against two state-of-the-art solutions of the MRTA and against two evolutionary methods under five different numerical simulations. The simulation results confirm that the proposed method is highly competitive in terms of the clustering time, clustering cost and MRTA time.

Practical implications

The proposed algorithm is quite useful for real-world applications, especially the scenarios involving a high number of robots and tasks.

Originality/value

In this methodology, owing to the ACD3GPSO algorithm, task allocation's run time has diminished. Therefore, the proposed method can be considered as a vital alternative in the field of MRTA with growing numbers of both robots and tasks. In PSO, stagnation and local optima issues are avoided by adding assorted variety to the population, without losing its fast convergence.
Basel III in Africa: making it work
Authors: Ozili Peterson K.
Published: September 2019

Purpose

Basel III is a framework to protect the global banking system. The purpose of this paper is to provide a policy discussion on Basel III in Africa.

Design/methodology/approach

The significance of Basel III is discussed, and some ideas to consider when implementing Basel III to make it work in Africa, are provided.

Findings

Under Basel III, the African banking industry should expect better capital quality, higher capital levels, minimum liquidity requirement for banks, reduced systemic risk and differences in Basel III transitional arrangements. This paper also emphasizes that there should be enough time for the transition to Basel III in Africa; a combination of micro and macro-prudential regulations is needed; and the need to repair the balance sheets of banks, in preparation for Basel III.

Originality/value

The discussions in this paper will benefit policymakers, academics and other stakeholders interested in financial regulation in Africa such as the World bank and the International Monetary Fund.
Numerical study of obstacle geometry effect on the vortex shedding suppression and aerodynamic characteristics
Authors: Fezai Salwa , Ben-Cheikh Nader , Ben-Beya Brahim , Lili Taieb
Published: September 2019

Purpose

Two-dimensional incompressible fluid flows around a rectangular shape placed over a larger rectangular shape at low Reynolds numbers (Re) have been numerically analyzed in the present work. The vortex shedding is investigated at different arrangements of the two shapes allowing the investigation of three possible configurations. The calculations are carried out for several values of Re ranging from 1 to 200. The effect of the obstacle geometry on the vortex shedding is analyzed for crawling, steady and unsteady regimes. The analysis of the flow evolution shows that with increasing Re beyond a certain critical value, the flow becomes unstable and undergoes a bifurcation. This paper aims to observe that the transition of the unsteady regime is performed by a Hopf bifurcation. The critical Re beyond which the flow becomes unsteady is determined for each configuration. A special attention is paid to compute the drag and lift forces acting on the rectangular shapes, which allowed determining; the best configuration in terms of both drag and lift. The unsteady periodic wake is characterized by the Strouhal number, which varies with the Re and the obstacle geometry. Hence, the values of vortex shedding frequencies are calculated in this work.

Design/methodology/approach

The dimensionless Navier–Stokes equations were numerically solved using the following numerical technique based on the finite volume method. The temporal discretization of the time derivative is performed by an Euler backward second-order implicit scheme. Non-linear terms are evaluated explicitly; while, viscous terms are treated implicitly. The strong velocity–pressure coupling present in the continuity and the momentum equations are handled by implementing the projection method.

Findings

The present paper aims to numerically study the effect of the obstacle geometry on the vortex shedding and on the drag and lift forces to analyze the flow structure around three configurations at crawling, steady and unsteady regimes.

Originality/value

A special attention is paid to compute the drag and lift forces acting on the rectangular shapes, which allowed determining; the best shapes configuration in terms of both drag and lift.
Parallel two-step finite element algorithm based on fully overlapping domain decomposition for the time-dependent natural convection problem
Authors: Ping Yuan , Su Haiyan , Zhao Jianping , Feng Xinlong
Published: September 2019

Purpose

This paper aims to propose two parallel two-step finite element algorithms based on fully overlapping domain decomposition for solving the 2D/3D time-dependent natural convection problem.

Design/methodology/approach

The first-order implicit Euler formula and second-order Crank–Nicolson formula are used to time discretization respectively. Each processor of the algorithms computes a stabilized solution in its own global composite mesh in parallel. These algorithms compute a nonlinear system for the velocity, pressure and temperature based on a lower-order element pair (P1b-P1-P1) and solve a linear approximation based on a higher-order element pair (P2-P1-P2) on the same mesh, which shows that the new algorithms have the same convergence rate as the two-step finite element methods. What is more, the stability analysis of the proposed algorithms is derived. Finally, numerical experiments are presented to demonstrate the efficacy and accuracy of the proposed algorithms.

Findings

Finally, numerical experiments are presented to demonstrate the efficacy and accuracy of the proposed algorithms.

Originality/value

The novel parallel two-step algorithms for incompressible natural convection problem are proposed. The rigorous analysis of the stability is given for the proposed parallel two-step algorithms. Extensive 2D/3D numerical tests demonstrate that the parallel two-step algorithms can deal with the incompressible natural convection problem for high Rayleigh number well.