bluuebunny/crossref_metadata_2025 huggingface dataset:
High-throughput analysis of single human cells reveals the complex nature of DNA replication timing control
Authors: Massey Dashiell J. , Koren Amnon
Published: May 2021

DNA replication initiates from replication origins firing throughout S phase. Debate remains about whether origins are a fixed set of loci, or a loose agglomeration of potential sites used stochastically in individual cells, and about how consistent their firing time is. We developed an approach to profile DNA replication from whole-genome sequencing of thousands of single cells, which includes “in silico flow cytometry”, a method for discriminating replicating and non-replicating cells. Using two microfluidic platforms, we analyzed up to 2,437 replicating cells from a single sample. The resolution and scale of the data allow focused analysis of replication initiation sites, demonstrating that most occur in confined genomic regions. While initiation order is remarkably similar across cells, we unexpectedly identify several subtypes of initiation regions in late-replicating regions. Taken together, high throughput, high resolution sequencing of individual cells reveals previously underappreciated variability in replication initiation and progression.
S-Palmitoylation-Dependent Regulation of Cardiomyocyte Rac1 Signaling Activity and Cardiac Hypertrophy
Authors: Brody Matthew J. , Baldwin Tanya A. , Subramani Arasakumar , Kanisicak Onur , Vagnozzi Ronald J. , Molkentin Jeffery D.
Published: May 2021

S-palmitoylation is a reversible lipid modification that regulates trafficking, localization, activity, and/or stability of protein substrates by serving as a fatty acid anchor to cell membranes. However, S-palmitoylation-dependent control of signal transduction in cardiomyocytes and its effects on cardiac physiology are not well understood. We performed an in vivo gain-of-function screen of zinc finger Asp-His-His-Cys (zDHHC) family S-acyl transferases that catalyze S-palmitoylation and identified the Golgi-localized enzyme zDHHC3 as a critical regulator of cardiac maladaptation. The closely-related enzyme, zDHHC7, also induced severe cardiomyopathy but this effect was not observed with overexpression of plasma membrane enzyme zDHHC5, endoplasmic reticulum enzyme zDHHC6, or Golgi enzyme zDHHC13. To identify effectors that may underlie zDHHC3-induced cardiomyopathy we performed quantitative site-specific S-acyl proteomics in zDHHC3-overexpressing cells that revealed the small GTPase Rac1 as a novel substrate. We generated cardiomyocyte-specific transgenic mice overexpressing zDHHC3, which develop severe cardiac disease. Cardiomyopathy and congestive heart failure in zDHHC3 transgenic mice are preceded by enhanced S-palmitoylation of Rac1 and induction of additional Rho family small GTPases including RhoA, Cdc42, and the Rho family-specific chaperone RhoGDI. In contrast, transgenic mice overexpressing an enzymatically-dead mutant of zDHHC3 do not exhibit this profound induction of RhoGTPase signaling or develop cardiac disease. Rac1 S-palmitoylation, plasma membrane localization, activity, and downstream hypertrophic signaling were substantially increased in zDHHC3 overexpressing hearts. Taken together, these data suggest inhibition of zDHHC3/7 S-acyl transferase activity at the cardiomyocyte Golgi or disruption of Rac1 S-palmitoylation as novel therapeutic strategies to treat cardiac disease or other diseases associated with enhanced RhoGTPase signaling.
CD147 antibody specifically and effectively inhibits infection and cytokine storm of SARS-CoV-2 variants
Authors: Geng Jiejie , Chen Liang , Yuan Yufeng , Chen Ruo , Wang Ke , Deng Yongqiang , Du Peng , Liu Jiangning , Wu Guizhen , Wang Youchun , Xu Ke , Sun Xiuxuan , Guo Ting , Yang Xu , Wu Jiao , Jiang Jianli , Li Ling , Zhang Jun , Zhang Kui , Zhu Hua , Zheng Zhaohui , Fu Xianghui , Yang Fengfan , Chen Xiaochun , Tang Hao , Zhang Zheng , Wei Ding , Zhang Yang , Shi Ying , Zhu Yumeng , Pei Zhuo , Huo Fei , Chen Shirui , Wang Qingyi , Xie Wen , Li Yirong , Shi Mingyan , Bian Huijie , Zhu Ping , Chen Zhi-Nan
Published: May 2021

SARS-CoV-2 and its variants are raging worldwide. Unfortunately, the global vaccination is not efficient enough to attain a vaccine-based herd-immunity and yet no special and effective drug is developed to contain the spread of the disease. Previously we have identified CD147 as a novel receptor for SARS-CoV-2 infection. Here, we demonstrated that CD147 antibody effectively inhibits infection and cytokine storm caused by SARS-CoV-2 variants. In CD147KOVeroE6 cells, infections of SARS-CoV-2, its variants (B.1.1.7, B.1.351) and pseudovirus mutants (B.1.1.7, B.1.351, B.1.525, B.1.526 (S477N), B.1.526 (E484K), P.1, P.2, B.1.617.1, B.1.617.2) were decreased. Meanwhile, CD147 antibody effectively blocked the entry of variants and pseudomutants in VeroE6 cells, and inhibited the expression of cytokines. A model of SARS-CoV-2-infected hCD147 transgenic mice was constructed, which recapitulated the features of exudative diffuse alveolar damage and dynamic immune responses of COVID-19. CD147 antibody could effectively clear the virus and alveolar exudation, resolving the pneumonia. We found the elevated level of cyclophilin A (CyPA) in plasma of severe/critical cases, and identified CyPA as the most important proinflammatory intermediate causing cytokine storm. Mechanistically, spike protein of SARS-CoV-2 bound to CD147 and initiated the JAK-STAT pathway, which induced expression of CyPA. CyPA reciprocally bound to CD147, triggered MAPK pathway and consequently mediated the expression of cytokine and chemokine. In conclusion, CD147 is a critical target for SARS-CoV-2 variants and CD147 antibody is a promising drug to control the new wave of COVID-19 epidemic.
Yin Yang 1 sets up the stage for cerebellar astrocyte maturation
Authors: Mockenhaupt Karli , Tyc Katarzyna M. , McQuiston Adam , Hariprashad Avani , Biswas Debolina D. , Gupta Angela S. , Olex Amy L. , Singh Sandeep K. , Waters Michael R. , Dupree Jeff L. , Dozmorov Mikhail G. , Kordula Tomasz
Published: May 2021

Diverse subpopulations of astrocytes tile different brain regions to accommodate local requirements of neurons and associated neuronal circuits. Nevertheless, molecular mechanisms governing astrocyte diversity remain mostly unknown. We explored the role of a zinc finger transcription factor Yin Yang 1 (YY1) that is expressed in astrocytes. We found that specific deletion of YY1 from astrocytes causes severe motor deficits in mice, induces Bergmann gliosis, and results in simultaneous loss of GFAP expression in velate and fibrous cerebellar astrocytes. Single cell RNA-seq analysis showed that YY1 exerts specific effects on gene expression in subpopulations of cerebellar astrocytes. We found that although YY1 is dispensable for the initial stages of astrocyte development, it regulates subtype-specific gene expression during astrocyte maturation. Moreover, YY1 is continuously needed to maintain mature astrocytes in the adult cerebellum. Our findings suggest that YY1 plays critical roles regulating cerebellar astrocyte maturation during development and maintaining a mature phenotype of astrocytes in the adult cerebellum.
Mad1’s ability to interact with Mad2 is essential to regulate and monitor meiotic synapsis in C. elegans
Authors: Devigne Alice , Bhalla Needhi
Published: May 2021

Meiotic homolog synapsis is essential to ensure accurate segregation of chromosomes during meiosis. In C. elegans, synapsis and a checkpoint that monitors synapsis relies on the spindle checkpoint components, Mad1 and Mad2, and Pairing Centers (PCs), cis-acting loci that interact with the nuclear envelope to mobilize chromosomes within the nucleus. Here, we show that mutations in some spindle checkpoint mutants affect PC movement early in meiotic prophase, consistent with a link between PC mobility and the regulation of synapsis. Further, we test what specific functions of Mad1 and Mad2 are required to regulate and monitor synapsis. We find that a mutation that abrogates Mad1’s localization to the nuclear periphery abolishes the synapsis checkpoint but has no effect on Mad2’s localization to the nuclear periphery or synapsis. By contrast, a mutation that prevents Mad1’s interaction with Mad2 abolishes the synapsis checkpoint, delays synapsis and fails to localize Mad2 to the nuclear periphery. These data indicate that Mad1’s primary role in regulating synapsis is through control of Mad2 and that Mad2 can bind other factors at the nuclear periphery. We also tested whether Mad2’s ability to adopt a specific conformation associated with its activity during spindle checkpoint function is required for its role in meiosis. A mutation that prevents Mad2 from adopting its active conformer fails to localize to the nuclear periphery, abolishes the synapsis checkpoint and exhibits substantial defects in meiotic synapsis. Thus, Mad2, and its regulation by Mad1, is a major regulator of meiotic synapsis in C. elegans.

AUTHOR SUMMARY

Sexual reproduction relies on production of gametes, such as eggs and sperm, which are produced during meiosis. During this specialized cell division, chromosomes replicate, pair with their homologs, undergo synapsis and finally undergo recombination, all of which are required for correct meiotic chromosome segregation. Chromosomes are highly mobile during these steps in meiosis but the specific role of this mobility is unclear. Here, we show that spindle assembly checkpoint proteins, Mad1 and Bub3, that regulate and monitor meiotic synapsis are implicated in chromosome movement, solidifying the functional link between chromosome mobility and synapsis. Moreover, we provide additional data that another spindle checkpoint effector, Mad2, and its regulation by Mad1, plays an important role in regulating meiotic synapsis.
Two microbiota subtypes identified in Irritable Bowel Syndrome with distinct responses to the low-FODMAP diet
Authors: Vervier Kevin , Moss Stephen , Kumar Nitin , Adoum Anne , Barne Meg , Browne Hilary , Kaser Arthur , Kiely Chris , Neville Anne , Powell Nina , Raine Tim , Stares Mark D. , Zhu Ana , De La Revilla Negro Juan , Lawley Trevor , Parkes Miles
Published: May 2021

Objective

Reducing FODMAPs can be clinically beneficial in IBS but the mechanism is poorly understood. We aimed to detect microbial signatures that might predict response to the low FODMAP diet and assess whether microbiota compositional and functional shifts could provide insights into its mode of action.

Design

We used metagenomics to determine high-resolution taxonomic and functional profiles of the stool microbiota from IBS cases and household controls (n=56 pairs) on their usual diet. Clinical response and microbiota changes were studied in 41 pairs after 4 weeks on a low FODMAP diet.

Results

Unsupervised analysis of baseline IBS cases pre-diet identified two distinct microbiota profiles, which we refer to as IBSP(pathogenic-like) and IBSH(health-like) subtypes. IBSPmicrobiomes were enriched in Firmicutes and genes for amino acid and carbohydrate metabolism, but depleted in Bacteroidetes species. IBSHmicrobiomes were similar to controls. On the low FODMAP diet IBSHand control microbiota were unaffected, but the IBSPsignature shifted towards a health-associated microbiome with an increase in Bacteroidetes (p=0.009), a decrease in Firmicutes species (p=0.004) and normalization of primary metabolic genes. The clinical response to the low FODMAP diet was greater in IBSPsubjects compared to IBSH(p = 0.02).

Conclusion

50% of IBS cases manifested a ‘pathogenic’ gut microbial signature. This shifted towards the healthy profile on the low FODMAP diet; and IBSPcases showed an enhanced clinical responsiveness to the dietary therapy. The effectiveness of FODMAP exclusion in IBSPmay result from the alterations in gut microbiota and metabolites produced. Microbiota signatures could be useful as biomarkers to guide IBS treatment; and investigating IBSPspecies and metabolic pathways might yield insights regarding IBS pathogenic mechanisms.

Significance of this study

What is already known on this subject?

IBS subjects often respond to a low FODMAP diet.

The gut microbiota has been implicated in IBS.

The microbiota in IBS subjects may change with diet.

What are the new findings?

We were able to stratify patients with IBS according to their gut microbiota species and metabolic gene signatures.

We identified a distinct gut microbiota subtype with an enhanced clinical response to a low FODMAP diet compared to other IBS subjects.

How might it impact on clinical practice in the foreseeable future?

The potential development of a microbiota signature as a biomarker to manage IBS cases with a low FODMAP diet recommendation.

If the bacteria represented in the IBSPsubtype are shown to play a pathogenic role in IBS, perhaps through the metabolic activity this provides a target for new therapies and an intermediate phenotype by which to assess them.
Elucidating the correlation between the number of TTTTGAT heptamer repeats and cholera toxin promoter activity in Vibrio cholerae O1 pandemic strains
Authors: Naha Arindam , Withey Jeffrey H. , Mukherjee Piyali , Saha Rudra Narayan , Samanta Prosenjit , Ghosh Amit , Miyoshi Shin-ichi , Dutta Shanta , Mukhopadhyay Asish K.
Published: May 2021

A complex regulatory cascade controls expression of the cholera toxin genes (ctxAB) in Vibrio cholerae; which eventually leads to choleragen (CT) production and secretion, resulting in rice watery diarrhoea. The cholera toxin promoter (PctxAB) contains a series of heptad repeats (5’-TTTTGAT-3’); which have been previously shown to play crucial role in ctxAB transcriptional regulation by recruiting the transcriptional activators ToxT, ToxR, and the nucleoid-associated protein H-NS along the ctx promoter. The numbers of these repeats vary between the two biotypes of V. cholerae O1 strains, and even among strains of the same biotype. In this study, we examined PctxAB activation of V. cholerae O1 pandemic strains to understand the significance of the distal heptad repeats in regulating ctx expression. Interestingly, we found that ctx activation may depend on the number of TTTTGAT heptad repeats within PctxAB, and we posit that the occupation of the distal repeats by H-NS could further prevent transcriptional activation of ctx genes in V. cholerae. We hypothesize that ToxT-dependent transcriptional activation may not require entire displacement of H-NS and propose a revision in the currently accepted model of ToxT dependent PctxAB transcriptional activation.

IMPORTANCE

CT production by pathogenic V. cholerae O1 strains is regulated through the transcriptional silencing of CTX promoter by H-NS and counter repression by ToxT. The highly AT rich PctxAB is composed of the tandem repeats 5□ TTTTGAT 3□; the numbers of which differ among the classical and El Tor biotypes. However, it is still not very clear whether the numbers of these repeats could be correlated with promoter activation of the ctx operon. Here we report the role of the distal repeats in ctxAB expression levels. We demonstrate that PctxAB activation changes with the number of the heptad repats within the core promoter element, thereby suggesting a model for ctx regulation in the toxigenic strains of V. cholerae.
Elimination Of Aberrantly Specified Cell Clones Is Independent Of Interfacial Myosin II Accumulation
Authors: Klipa Olga , Hamaratoglu Fisun
Published: May 2021

Spatial organization of differently fated cells within an organ is essential and needs to be maintained during development. This is largely implemented via compartment boundaries that serve as barriers between distinct cell types. Biased accumulation of junctional non-muscle Myosin II along the interface between differently fated groups of cells contributes to boundary integrity and maintains its shape via increased tension [1-4]. Here we test whether interfacial Myosin driven tension is responsible for the elimination of aberrantly specified cells that would otherwise compromise compartment organization. To this end, we genetically reduce Myosin II levels in three different patterns: in both wild-type and misspecified cells, only in misspecified cells and specifically at the interface between wild-type and aberrantly specified cells. We find that recognition and elimination of aberrantly specified cells do not rely on tensile forces driven by interfacial Myosin cables. Moreover, apical constriction of misspecified cells and their separation from wild type neighbors occurs even when Myosin level is greatly reduced. Thus, we conclude that the forces that drive elimination of aberrantly specified cells are largely independent of Myosin II.
Human cytomegalovirus protein RL1 degrades the antiviral factor SLFN11 via recruitment of the CRL4 E3 ubiquitin ligase complex
Authors: Nightingale Katie , Fielding Ceri A. , Zerbe Cassie , Hunter Leah , Potts Martin , Fletcher-Etherington Alice , Nobre Luis , Wang Eddie C.Y. , Strang Blair L. , Houghton Jack , Antrobus Robin , Suarez Nicolas M. , Nichols Jenna , Davison Andrew J. , Stanton Richard J. , Weekes Michael P.
Published: May 2021

Human cytomegalovirus (HCMV) is an important human pathogen and a paradigm of viral immune evasion, targeting intrinsic, innate and adaptive immunity. We have employed two novel, orthogonal multiplexed tandem mass tag-based proteomic screens to identify host proteins downregulated by viral factors expressed during the latest phases of viral infection. This approach revealed that the HIV-1 restriction factor Schlafen-11 (SLFN11) was degraded by the poorly characterised, late-expressed HCMV protein RL1, via recruitment of the Cullin4-RING E3 Ubiquitin Ligase (CRL4) complex. SLFN11 potently restricted HCMV infection, inhibiting the formation and spread of viral plaques. Overall, we show that a restriction factor previously thought only to inhibit RNA viruses additionally restricts HCMV. We define the mechanism of viral antagonism and also describe an important resource for revealing additional molecules of importance in antiviral innate immunity and viral immune evasion.

Significance Statement

Previous proteomic analyses of host factors targeted for downregulation by HCMV have focused on early or intermediate stages of infection. Using multiplexed proteomics, we have systematically identified viral factors that target each host protein downregulated during the latest stage of infection, after the onset of viral DNA replication. Schlafen-11 (SLFN11), an interferon-stimulated gene and restriction factor for retroviruses and certain RNA viruses, potently restricted HCMV infection. Our discovery that the late-expressed HCMV protein RL1 targets SLFN11 for proteasomal degradation provides the first evidence for a viral antagonist of this critical cellular protein. We therefore redefine SLFN11 as an important factor that targets DNA viruses as well as RNA viruses, offering novel therapeutic potential via molecules that inhibit RL1-mediated SLFN11 degradation.
Evidence Of We-Representation In Monkeys When Acting Together
Authors: Lacal Irene , Babicola Lucy , Caminiti Roberto , Ferrari-Toniolo Simone , Schito Andrea , Nalbant Laura E. , Gupta Rajnish K. , Battaglia-Mayer Alexandra
Published: May 2021

A hallmark of successful evolution resides in the ability to adapt our actions to those of others, optimizing collective behaviour, to achieve goals otherwise unattainable by individuals acting alone. We have previously shown that macaques constitute a good model to analyse joint behavior, since they are able to coordinate their actions in a dyadic context. In the present work, we investigated whether monkeys could improve their joint-action performance, under special visuomotor conditions. The behavior of 5 monkeys was analyzed in isometric center-out tasks, requiring hand force application in different directions, either individually or together with a partner. Manipulating the presence or absence of a pre-instruction about the future action condition (SOLO or TOGETHER), allowed us to investigate on the existence of a “we-representation” in macaque monkeys. We found that pre-cueing the future action context increased the chances of dyadic success, also thanks to the emergence of an optimal kinematic setting, that ultimately facilitates inter-individual motor coordination. Our results offer empirical evidence in macaques of a “We-representation” during collective behavior, that once is cued in advance has an overall beneficial effect on joint performance.
Label-free super-resolution chemical imaging of biomedical specimens
Authors: Guilbert Julien , Negash Awoke , Labouesse Simon , Gigan Sylvain , Sentenac Anne , de Aguiar Hilton B.
Published: May 2021

Raman microscopy provides chemically selective imaging by exploiting intrinsic vibrational properties of specimens. Yet, a fast acquisition, low phototoxicity, and non-specific (to a vibrational/electronic mode) super-resolution method has been elusive for tissue imaging. We demonstrate a single-pixel-based approach, combined with robust structured illumination, that enables fast super-resolution in stimulated Raman scattering microscopy at low power levels. The methodology is straightforward to implement and compatible with thick biological specimens, therefore paving the way for probing complex biological systems when exogenous labelling is challenging.
Glucosidase inhibitors suppress SARS-CoV-2 in tissue culture and may potentiate
Authors: Reyes Hanako , Du Yanming , Zhou Tianlun , Xie Xuping , Shi Pei Yong , Weiss Susan , Block Timothy M.
Published: May 2021

Iminosugar glucosidase inhibitors prevent the folding of a range of viral N-linked glycoproteins, ranging from hepatitis B to Ebola. We recently showed they inhibit folding and function of the ACE2 protein, which is the receptor for SARS-CoV-2, and they have also inhibited the SARS Spike polypeptides. Here we report that the imino sugar glucosidase inhibitors, N-butyl deoxynojirimycin (NBDNJ), which is approved for management of lysosomal storage disease (sold as Zavesca), and ureido-N-hexyl deoxynojirimycine (BSBI-19029), suppress the replication of SARS-ncCoV-2/USA/WA1/2020 strain, in tissue culture. Moreover, combinations of either of these iminosugars with Remdesivir were particularly potent in suppressing SARS-CoV-2. Briefly, NBDNJ, 19029 and Remdesivir suppressed SARS-CoV-2 production in A549ACE2human lung cells with IC90s of ~130 μM, ~4.0 μM, and 0.006 μM respectively. The combination of as little as 0.037 μM of NBDNJ or 0.04 μM 19029, respectively and 0.002 μM Remdesivir yielded IC90s. Medical strategies to manage SARS-CoV-2 infection of people are urgently needed, and although Remdesivir and Favipiravir have shown efficacy, it is limited. NBDNJ was recently reported by others to have tissue culture activity against SARS-CoV-2, so our report confirms this, and extends the findings to a more potent iminosugar, 19029 and combination with Remdesivir. Since both NBDNJ and Remdesivir are both approved and available for human use, the possibility that NBDNJ has mono therapeutic value against SARS-CoV-2 as well as can enhance Remdesivir, may have clinical implications, which are discussed, here.
Gene- and genome-centric dynamics shape the diversity of oral bacterial populations
Authors: Utter Daniel R. , Cavanaugh Colleen M. , Borisy Gary G.
Published: May 2021

Two major viewpoints have been put forward for how microbes adapt to a niche, differing in whether adaptation is driven principally by gene-centric or genome-centric processes. Longitudinal sampling at microbially-relevant timescales, i.e., days to weeks, is critical for distinguishing these mechanisms. Because of its significance for both microbial ecology and human health and its accessibility and high level of curation, we used the oral microbiota to evaluate evolutionary mechanisms. Metagenomes were generated by shotgun sequencing of total community DNA from the healthy tongues of 17 volunteers at four to seven timepoints obtained over intervals of days to weeks. We obtained 390 high-quality metagenome-assembled genomes (MAGs) defining population genomes from 55 genera, the majority of which were temporally stable at the MAG level. Decomposing MAG-defined populations by single nucleotide variant frequencies revealed MAGs were composed of up to 5 haplotypes, putatively distinct strain- or subpopulation-level genotypes. Most haplotypes were stable over time, yet we found examples of individual haplotypes sweeping from low abundance to dominance in a population over a period of days, a pattern suggestive of genome-centric adaptation. At the gene level, the vast majority of genes in each MAG were tightly linked over the two-week sampling window based on their frequency in the metagenomes of different mouths. The few genes that changed in abundance independently from nearby genes did not change in a directional manner, nor did nonsynonymous codon variants within such genes. Altogether, these observations characterize the intrapopulation genomic dynamics of the oral microbiota at microbially-relevant timescales. Our results demonstrate that both gene- and genome-wide sweeps occur on daily timescales but likely with different ecological ramifications. We infer that genome-wide selection of ecotypes is the dominant mode of adaptation in the oral populations, with short-term changes in gene frequency also occurring.
Plasmid co-infection: linking biological mechanisms to ecological and evolutionary dynamics
Authors: Igler Claudia , Huisman Jana S. , Siedentop Berit , Bonhoeffer Sebastian , Lehtinen Sonja
Published: May 2021

As infectious agents of bacteria and vehicles of horizontal gene transfer, plasmids play a key role in bacterial ecology and evolution. Plasmid dynamics are shaped not only by plasmid-host interactions, but also by ecological interactions between plasmid variants. These interactions are complex: plasmids can co-infect the same host cell and the consequences for the co-resident plasmid can be either beneficial or detrimental. Many of the biological processes that govern plasmid co-infection–from systems to exclude infection by other plasmids to interactions in the regulation of plasmid copy number per cell–are well characterised at a mechanistic level. Modelling plays a central role in translating such mechanistic insights into predictions about plasmid dynamics, and in turn, the impact of these dynamics on bacterial evolution. Theoretical work in evolutionary epidemiology has shown that formulating models of co-infection is not trivial, as some modelling choices can introduce unintended ecological assumptions. Here, we review how the biological processes that govern co-infection can be represented in a mathematical model, discuss potential modelling pitfalls, and analyse this model to provide general insights into how co-infection impacts eco-evolutionary outcomes. In particular, we demonstrate how beneficial and detrimental effects of co-infection give rise to frequency-dependent selection.
Functional characterization of splicing regulatory elements
Authors: Adamson SI , Zhan L , Graveley BR
Published: May 2021

Background

RNA binding protein-RNA interactions mediate a variety of processes including pre-mRNA splicing, translation, decay, polyadenylation and many others. Previous high-throughput studies have characterized general sequence features associated with increased and decreased splicing of certain exons, but these studies are limited by not knowing the mechanisms, and in particular, the mediating RNA binding proteins, underlying these associations.

Results

Here we utilize ENCODE data from diverse data modalities to identify functional splicing regulatory elements and their associated RNA binding proteins. We identify features which make splicing events more sensitive to depletion of RNA binding proteins, as well as which RNA binding proteins act as splicing regulators sensitive to depletion. To analyze the sequence determinants underlying RBP-RNA interactions impacting splicing, we assay tens of thousands of sequence variants in a high-throughput splicing reporter called Vex-seq and confirm a small subset in their endogenous loci using CRISPR base editors. Finally, we leverage other large transcriptomic datasets to confirm the importance of RNA binding proteins which we designed experiments around and identify additional RBPs which may act as additional splicing regulators of the exons studied.

Conclusions

This study identifies sequence and other features underlying splicing regulation mediated specific RNA binding proteins, as well as validates and identifies other potentially important regulators of splicing in other large transcriptomic datasets.
Influence of educational programs oriented toward entrepreneurship on the entrepreneurial intention of university students: the case of Chile
Authors: Silva Noah , Fernández‐Robin Cristóbal , Yáñez Diego , Romaní Gianni
Published: May 2021

Purpose

This study measures the influence of educational programs oriented toward entrepreneurship (POE) on the prediction of the entrepreneurial intention (EI) of university students, based on the theory of planned behaviour (TPB).

Design/methodology/focus

The sample contains a total of 4,697 answers from university students, obtained through the 2018 Global University Entrepreneurial Spirit Students' Survey (GUESSS) project. A model of structural equations was used.

Findings

The results show that educational POE have an impact on EI, mediated by the perceived university environment (UE) and entrepreneurial skills (ES). In addition, it was confirmed that the variable that best explains EI is the attitude toward entrepreneurship (ATE), followed by perceived behavioral control (PBC); these two variables are able to mediate the effect of subjective norm (SN) on EI.

Research limitations/implications

The study is limited to students in higher education. Additionally, the data used come from only one country.

Practical implications

Educational POE that are focused on providing and improving ES and knowledge must be promoted, given that they indirectly strengthen the EI of students in higher education.

Originality/value

The effect of educational POE, mediated by ES and the UE, on EI is measured.
Total quality management and sustainability in the public service sector: the mediating effect of service innovation
Authors: Ali AlShehail Ohoud , Khan Mehmood , Ajmal Mian
Published: May 2021

Purpose

This study aims to critically investigate the structural relationships between total quality management (TQM), service innovation and sustainability performance in the public service sector of the United Arab Emirates (UAE).

Design/methodology/approach

The study employed an online survey to collect data from 400 employees working in eight selected UAE public service sector organisations located in Abu Dhabi. The collected data were analysed using structural equation modelling (SEM) to empirically examine whether TQM practices improve service innovation and, subsequently, sustainability performance in the UAE's public service sector.

Findings

The results show that TQM has a significant impact on service innovation and sustainability performance in the UAE's public service sector. Additionally, service innovation partially mediates the relationship between TQM and sustainability performance.

Practical implications

The public service sector's TQM practices and service innovation in the UAE have a much greater impact on social and environmental sustainability than on economic sustainability performance. Adopting five dimensions of TQM (following the Abu Dhabi Award for Excellence in Government Performance [ADAEP] model) across the UAE's public organisations will enable government departments to deliver innovative services to its beneficiaries.

Originality/value

This study provides a substantial contribution by addressing the gaps in the literature. Very few studies have empirically investigated the possible association between TQM, service innovation and sustainability performance in public sector organisations, particularly in developing countries such as the UAE, where the increasing efforts in TQM practices are still in their emerging stages, mainly targeting innovative service offerings and sustainable performance.
A new response surface method based on the adaptive bivariate cut-HDMR
Authors: Fan Wenliang , Shen Wei , Zhang Qingbin , Ang Alfredo H.-S.
Published: May 2021

Purpose

The purpose of this study is to improve the efficiency and accuracy of response surface method (RSM), as well as its robustness.

Design/methodology/approach

By introducing cut-high-dimensional representation model (HDMR), the delineation of cross terms and the constitution analysis of component function, a new adaptive RSM is presented for reliability calculation, where a sampling scheme is also proposed to help constructing response surface close to limit-state.

Findings

The proposed method has a more feasible process of evaluating undetermined coefficients of each component function than traditional RSM, and performs well in terms of balancing the efficiency and accuracy when compared to the traditional second-order polynomial RSM. Moreover, the proposed method is robust on the parameter in a wide range, indicating that it is able to obtain convergent result in a wide feasible domain of sample points.

Originality/value

This study constructed an adaptive bivariate cut-HDMR by introducing delineation of cross-terms and constitution of univariate component function; and a new sampling technique is proposed.
On the topological enrichment for crack modeling via the generalized/extended FEM: a novel discussion considering smooth partitions of unity
Authors: Torres Diego Amadeu F.
Published: May 2021

Purpose

It has been usual to prefer an enrichment pattern independent of the mesh when applying singular functions in the Generalized/eXtended finite element method (G/XFEM). This choice, when modeling crack tip singularities through extrinsic enrichment, has been understood as the only way to surpass the typical poor convergence rate obtained with the finite element method (FEM), on uniform or quasi-uniform meshes conforming to the crack. Then, the purpose of this study is to revisit the topological enrichment strategy in the light of a higher-order continuity obtained with a smooth partition of unity (PoU). Aiming to verify the smoothness' impacts on the blending phenomenon, a series of numerical experiments is conceived to compare the two GFEM versions: the conventional one, based on piecewise continuous PoU's, and another which considers PoU's with high-regularity.

Design/methodology/approach

The stress approximations right at the crack tip vicinity are qualified by focusing on crack severity parameters. For this purpose, the material forces method originated from the configurational mechanics is employed. Some attempts to improve solution using different polynomial enrichment schemes, besides the singular one, are discussed aiming to verify the transition/blending effects. A classical two-dimensional problem of the linear elastic fracture mechanics (LEFM) is solved, considering the pure mode I and the mixed-mode loadings.

Findings

The results reveal that, in the presence of smooth PoU's, the topological enrichment can still be considered as a suitable strategy for extrinsic enrichment. First, because such an enrichment pattern still can treat the crack independently of the mesh and deliver some advantage in terms of convergence rates, under certain conditions, when compared to the conventional FEM. Second, because the topological pattern demands fewer degrees of freedom and impacts conditioning less than the geometrical strategy.

Originality/value

Several outputs are presented, considering estimations for the

J–integral and the angle of probable crack advance, this last computed from two different strategies to monitoring blending/transition effects, besides some comments about conditioning. Both h- and p-behaviors are displayed to allow a discussion from different points of view concerning the topological enrichment in smooth GFEM.
A fast workpiece detection method based on multi-feature fused SSD
Authors: Shi Guoyuan , Zhang Yingjie , Zeng Manni
Published: May 2021

Purpose

Workpiece sorting is a key link in industrial production lines. The vision-based workpiece sorting system is non-contact and widely applicable. The detection and recognition of workpieces are the key technologies of the workpiece sorting system. To introduce deep learning algorithms into workpiece detection and improve detection accuracy, this paper aims to propose a workpiece detection algorithm based on the single-shot multi-box detector (SSD).

Design/methodology/approach

Propose a multi-feature fused SSD network for fast workpiece detection. First, the multi-view CAD rendering images of the workpiece are used as deep learning data sets. Second, the visual geometry group network was trained for workpiece recognition to identify the category of the workpiece. Third, this study designs a multi-level feature fusion method to improve the detection accuracy of SSD (especially for small objects); specifically, a feature fusion module is added, which uses “element-wise sum” and “concatenation operation” to combine the information of shallow features and deep features.

Findings

Experimental results show that the actual workpiece detection accuracy of the method can reach 96% and the speed can reach 41 frames per second. Compared with the original SSD, the method improves the accuracy by 7% and improves the detection performance of small objects.

Originality/value

This paper innovatively introduces the SSD detection algorithm into workpiece detection in industrial scenarios and improves it. A feature fusion module has been added to combine the information of shallow features and deep features. The multi-feature fused SSD network proves the feasibility and practicality of introducing deep learning algorithms into workpiece sorting.
Ambiguity factors in construction contracts entailing conflicts
Authors: Koc Kerim , Gurgun Asli Pelin
Published: May 2021

Purpose

Conflicts, claims and disputes are inherent in most construction projects. Acceptable degree of commonality in the interpretation of contract provisions is critical in effective contract administration. This study aims to assess the effects of contract ambiguity factors on construction conflicts, highlighting the causes of divergent interpretations using fuzzy technique for order of preference by the similarity-to-ideal-solution (TOPSIS) method.

Design/methodology/approach

Fuzzy TOPSIS framework with 27 ambiguity factors is constructed by conducting a comprehensive literature review, accompanied by a pilot study. Questionnaire survey is formed, and one-to-one interviews are arranged with 35 contract administration experts.

Findings

The findings indicate that (1) ambiguity due to excessive changes in the bill of quantity (BOQ) (including ambiguous provisions related to BOQ changes), (2) incomplete clauses that do not describe the scope of the intended work purely, (3) ambiguity due to excessive amendments in the scope of works (including ambiguous provisions related to scope changes), (4) ambiguous enforceability including excessive demands and (5) ambiguous goal and performance requirements are the top five ambiguity factors affecting construction conflicts.

Research limitations/implications

Presented framework is performed referring to ambiguity factors in all type of construction contracts in the general sense. However, the identified factors may vary depending on the project type, contract type, procurement method or use of standard contract forms (such as NEC, FIDIC).

Originality/value

The literature lacks the investigation of ambiguity factors in construction contracts, yet the assessment of the effects of contract ambiguity is essential to minimize conflicts.
The application of simulation in lean production research: a critical review and future directions
Authors: Shou Wenchi , Wang Jun , Wu Peng
Published: May 2021

Purpose

Simulation has attracted increasing attention in lean production research as a response to address the complexities of the production environment and difficulties of dealing with changes within a system. Considerable growth of using simulation to facilitate lean acceptance and implementation has been observed across different projects and sectors. However, a thorough review of the development and use of simulation in lean production research is limited.

Design/methodology/approach

This study aims to address this gap by reviewing 311 journal papers published in the past two decades on this specific research area and identify the state-of-the-art development and propose future research directions.

Findings

The review shows that current studies related to simulation in lean production research can be categorised into two major research streams, namely, simulation assisted lean facilitation and evaluation, and simulation-based lean education and training. Under the first research stream, a total of 19 application areas have been identified which applied both lean and simulation in their studies. The evolution of the simulation techniques used in these studies has been analysed as well. Meanwhile, four types of simulation games have been identified in the stream of simulation-based lean education and training and the impact and applicability of the different simulation and games have been discussed. A framework for engaging lean and simulation is suggested based on the review of the existing studies. The analysis in both streams also highlights the importance of stakeholder engagement and the utilisation of information technologies for future studies.

Practical implications

The findings of this study are expected to provide useful references for the future development and application of simulation in lean production research.

Originality/value

This paper conducted a broad and extensive review of simulation integrated lean production research. An in-depth examination of the retrieved papers was conducted through a structured and quantitative analysis to understand the current body of knowledge.
Development and implementation of a framework for estimating the economic benefits of an accessible and inclusive society
Authors: Tompa Emile , Mofidi Amirabbas , Jetha Arif , Lahey Pamela , Buettgen Alexis
Published: May 2021

Purpose

To develop a framework for estimating the economic benefits of an accessible and inclusive society and implement it for the Canadian context. The framework measures the gap between the current situation in terms of accessibility and inclusiveness, and a counterfactual scenario of a fully accessible and inclusive society.

Design/methodology/approach

The method consists of three steps. First, the conceptual framework was developed based on a literature review and expert knowledge. Second, the magnitudes for each domain of the framework was estimated for the reference year 2017 using data from various sources. Third, several sensitivity analyses were run using different assumptions and scenarios.

Findings

It was estimated that moving to a fully accessible and inclusive society would create a value of $337.7bn (with a range of $252.8–$422.7bn) for Canadian society in the reference year of 2017. This is a sizeable proportion of gross domestic product (17.6%, with a range of 13.1–22.0%) and is likely a conservative estimate of the potential benefits.

Originality/value

Understanding the magnitude of the economic benefits of an accessible and inclusive society can be extremely useful for governments, disability advocates and industry leaders as it provides invaluable information on the benefits of efforts, such as legislation, policies, programs and practices, to improve accessibility and inclusion of persons with disabilities. Furthermore, the total economic benefits and the benefits per person with a disability can serve as inputs in economic evaluations and impact assessments.
Board characteristics and integrated reporting quality: evidence from ESG European companies
Authors: Chouaibi Salim , Chouaibi Yamina , Zouari Ghazi
Published: May 2021

Purpose

The aim of this study is to analyze the possible relationship between board characteristics and integrated reporting quality in an international setting.

Design/methodology/approach

To test the study's hypotheses, the authors applied linear regressions with a panel data, and the authors collected data from the Thomson Reuters database (ASSET4) and from the annual reports from European companies to analyze data of 253 listed companies selected from the environmental, social and governance (ESG) index between 2010 and 2019.

Findings

The reached empirical results prove to indicate well that both of the board size, independence and diversity appear to have a significantly positive effect on the integrated reporting quality. Noteworthy, also, is the fact that the appointment of an independent nonexecutive chairman is positively associated with the integrated reporting related quality, and holds for firms with a nonindependent chairman.

Practical implications

Beyond the theoretical implications, our study also has several practical implications. These findings are particularly relevant for managers, shareholders, and policymakers. Thus, stakeholders should consider the accuracy of disclosure in determining the optimal reporting strategy (reducing risk estimation, returns' stock volatility, increasing long-term shareholder value and reputation of the firm).

Originality/value

This article is motivated by the low number of works in the context about the corporate social responsibility and sustainability issues. It makes an important contribution to the academic literature by adding to the limited body of research on integrated reporting and corporate governance in an ESG company setting. The study is also important for practitioners seeking to improve the quality of their integrated reports.