bluuebunny/crossref_metadata_2025 huggingface dataset:
Elastase treatment of tendon specifically impacts the mechanical properties of the interfascicular matrix
Authors: Godinho Marta S. , Thorpe Chavaunne T. , Greenwald Steve E. , Screen Hazel R. C.
Published: September 2020

The tendon interfascicular matrix (IFM) binds tendon fascicles together. As a result of its low stiffness behaviour under small loads, it enables non-uniform loading and increased overall extensibility of tendon by facilitating fascicle sliding. This function is particularly important in energy storing tendons, with previous studies demonstrating enhanced extensibility, recovery and fatigue resistance in the IFM of energy storing compared to positional tendons. However, the compositional specialisations within the IFM that confer this behaviour remain to be elucidated. It is well established that the IFM is rich in elastin, therefore we sought to test the hypothesis that elastin depletion (following elastase treatment) will significantly impact IFM, but not fascicle, mechanical properties, reducing IFM resilience in all samples, but to a greater extent in younger tendons, which have a higher elastin content. Using a combination of quasi-static and fatigue testing, and optical imaging, we confirmed our hypothesis, demonstrating that elastin depletion resulted in significant decreases in IFM viscoelasticity, fatigue resistance and recoverability compared to untreated samples, with no significant changes to fascicle mechanics. Ageing had little effect on fascicle or IFM response to elastase treatment.

This study offers a first insight into the functional importance of elastin in regional specific tendon mechanics. It highlights the important contribution of elastin to IFM mechanical properties, demonstrating that maintenance of a functional elastin network within the IFM is essential to maintain IFM and thus tendon integrity.
Differential effect of ethanol intoxication on peripheral markers of cerebral injury in murine blunt TBI
Authors: Li Zhenghui , Zhang Jin , Halbgebauer Steffen , Chandrasekar Akila , Rehman Rida , Ludolph Albert , Boeckers Tobias , Huber-Lang Markus , Otto Markus , Roselli Francesco , Heuvel Florian olde
Published: September 2020

Blood-based biomarkers have proven to be a reliable measure of traumatic brain injury (TBI) severity and outcome, in both murine models and patients. In particular, neuron-specific enolase (NSE) and neurofilament light (NFL) have been investigated in the clinical setting post injury. Ethanol intoxication (EI) remains a significant comorbidity in TBI, with 30-40% of patients having a positive blood alcohol level (BAC) post TBI. The effect of ethanol on blood-based biomarkers on the prognosis and diagnosis of TBI remain unclear. In this study, we investigated the effect of EI on NSE and NFL and their correlation with blood-brain barrier (BBB) integrity in a murine model of TBI. We have used ultra-sensitive single molecule array technology (SIMOA) and ELISA methods to measure NFL, NSE and Claudin-5 concentrations in plasma 3h post TBI. We showed that both NFL and NSE were increased 3h post TBI. However, ethanol blood concentrations only showed an inverse correlation with NSE, but not NFL. Claudin-5 levels were increased post injury, but no difference was detected in EI. The Claudin-5 increase post TBI was correlated with NFL, but not with NSE. Thus, the data indicate that ethanol has a confined effect on biomarker release in the bloodstream and neuronal biomarkers reflect a different pathophysiology upon TBI.
The mobility of interfaces between monomers in dimeric bovine ATP synthase participates in the ultrastructure of inner mitochondrial membranes
Authors: Spikes Tobias E. , Montgomery Martin G. , Walker John E.
Published: September 2020

The ATP synthase complexes in mitochondria make the ATP required to sustain life by a rotary mechanism. Their membrane domains are embedded in the inner membranes of the organelle and they dimerize via interactions between their membrane domains. The dimers form extensive chains along the tips of the cristae with the two rows of monomeric catalytic domains extending into the mitochondrial matrix at an angle to each other. When the interaction between membrane domains is disrupted in living cells, the morphology of the cristae is affected severely. By analysis of particles of purified dimeric bovine ATP synthase by cryo-electron microscopy, we have shown that the angle between the central rotatory axes of the monomeric complexes varies betweenca. 76°andca. 95°. Some variations in this angle arise directly from the catalytic mechanism of the enzyme, and others are independent of catalysis. The monomer-monomer interaction is mediated mainly by j-subunits attached to the surface of wedge shaped protein-lipid structures in the membrane domain of the complex, and the angular variation arises from rotational and translational changes in this interaction, and combinations of both. The structures also suggest how the dimeric ATP synthases might be interacting with each other to form the characteristic rows along the tips of the cristae via other inter-wedge contacts, moulding themselves to the range of oligomeric arrangements observed by tomography of mitochondrial membranes, and at the same time allowing the ATP synthase to operate under the range of physiological conditions that influence the structure of the cristae.
The transmembrane domain of DWORF activates SERCA directly; P15 and W22 residues are essential
Authors: Li Ang , Stroik Daniel R. , Yuen Samantha L. , Kleinboehl Evan , Cornea Razvan L. , Thomas David D.
Published: September 2020

The Ca-ATPase isoform 2a (SERCA2a) re-sequesters cytosolic Ca2+into the sarcoplasmic reticulum (SR) of cardiac myocytes, enabling muscle relaxation during diastole. A central factor in heart failure is abnormally high cytosolic [Ca2+], resulting in pathophysiology and decreased cardiac performance. Therefore, augmentation of the SERCA2a Ca2+transport activity is a promising therapeutic approach. A novel transmembrane peptide, dwarf open reading frame (DWORF), is proposed to enhance SR Ca2+uptake and myocyte contractility by displacing the protein phospholamban (PLB) from its inhibitory site on SERCA2a. In the present study, we have developed several cell-based FRET biosensor systems for time-resolved FRET (TR-FRET) measurements of the protein-protein interactions and structural changes in SERCA2a complexes with PLB and/or DWORF. To test the hypothesis that DWORF competes with PLB to occupy the putative SERCA2a binding site, we transiently transfected DWORF into a stable cell line expressing SERCA2a labeled with green fluorescent protein (GFP, the FRET donor) and PLB labeled with red fluorescent protein (RFP, the FRET acceptor). We observed a significant decrease in FRET efficiency, consistent with a decrease in the fraction of SERCA2a bound to PLB. Functional analysis demonstrates that DWORF activates SERCA in both the presence and absence of PLB. Furthermore, using site-directed mutagenesis, we generated DWORF variants that do not activate SERCA, thus identifying residues that are necessary for functional SERCA2a-DWORF interactions. This work advances our mechanistic understanding of the regulation of SERCA2a by small transmembrane proteins and sets the stage for future therapeutic development in heart failure research.
Inferring intestinal mucosal immune cell associated microbiome species and microbiota-derived metabolites in inflammatory bowel disease
Authors: Narasimhan Rajagopalan Lakshmi , Throm Allison A. , Koshy Jesvin Joy , Saldanha Keith Metelo Raul , Chandranpillai Harikrishnan , Lal Rahul Deva , Kumravat Mausam , Kumar K M Ajaya , Batra Aneesh , Zhong Fei , Liu Jiajian
Published: September 2020

Inflammatory bowel disease (IBD) is a complex, chronic inflammatory disease of the gastrointestinal tract with subtypes Crohn’s disease (CD) and ulcerative colitis (UC). While evidence indicates IBD is characterized by alterations in the composition and abundance of the intestinal microbiome, the challenge remains to specify bacterial species and their metabolites associated with IBD pathogenesis. By the integration of microbiome multi-omics data and computational methods, we provide analyses and methods for the first time to identify microbiome species and their metabolites that are associated with the human intestine mucosal immune response in patients with CD and UC at a systems level. First, we identified seven gut bacterial species and seventeen metabolites that are significantly associated with Th17 cellular differentiation and immunity in patients with active CD by comparing with those obtained in inactive CD and non-IBD controls. The seven species areRuminococcus gnavus, Escherichia coli, Lachnospiraceae bacterium, Clostridium hathewayi, Bacteroides faecis, Bacteroides vulgatus, andAkkermansia muciniphila, and a few associated metabolites include the secondary bile acid lithocholate and three short-chain fatty acids (SCFAs): propionate, butyrate, and caproate. We next systematically characterized potential mechanistic relationships between the Th17-involved metabolites and bacterial species and further performed differential abundance analysis for both microbiome species and their metabolites in CD and UC relative to non-IBD controls with their metagenomic and metabolomic data. Based on the deconvolution of immune cell compositions from host intestinal bulk RNA-seq, we investigated changes in immune cell composition and abundance in CD and UC in comparison to non-IBD controls. Finally, we further extended our species and metabolite associations with immune cells from Th17 and Th2 cells to B cells, plasma B cells, plasmablasts, CD4+ T cells, and CD8+ T cells. While a set of associations of immune cells with bacterial species and metabolites was supported by published evidence, the new findings in this work will help to furthering our understanding of immune responses and pathogenesis in IBD.
JSTA: joint cell segmentation and cell type annotation for spatial transcriptomics
Authors: Littman Russell , Hemminger Zachary , Foreman Robert , Arneson Douglas , Zhang Guanglin , Gómez-Pinilla Fernando , Yang Xia , Wollman Roy
Published: September 2020

RNA hybridization based spatial transcriptomics provides unparalleled detection sensitivity. However, inaccuracies in segmentation of image volumes into cells cause misassignment of mRNAs which is a major source of errors. Here we develop JSTA, a computational framework for Joint cell Segmentation and cell Type Annotation that utilizes prior knowledge of cell-type specific gene expression. Simulation results show that leveraging existing cell type taxonomy increases RNA assignment accuracy by more than 45%. Using JSTA we were able to classify cells in the mouse hippocampus into 133 (sub)types revealing the spatial organization of CA1, CA3, and Sst neuron subtypes. Analysis of within cell subtype spatial differential gene expression of 80 candidate genes identified 43 with statistically significant spatial differential gene expression across 61 (sub)types. Overall, our work demonstrates that known cell type expression patterns can be leveraged to improve the accuracy of RNA hybridization based spatial transcriptomics while providing highly granular cell (sub)type information. The large number of newly discovered spatial gene expression patterns substantiates the need for accurate spatial transcriptomics measurements that can provide information beyond cell (sub)type labels.
DeepPPPred: An Ensemble of BERT, CNN, and RNN for Classifying Co-mentions of Proteins and Phenotypes
Authors: Shahri Morteza Pourreza , Lyon Katrina , Schearer Julia , Kahanda Indika
Published: September 2020

The biomedical literature provides an extensive source of information in the form of unstructured text. One of the most important types of information hidden in biomedical literature is the relationships between human proteins and their phenotypes, which, due to the exponential growth of publications, can remain hidden. This provides a range of opportunities for the development of computational methods to extract the biomedical relationships from the unstructured text. In our previous work, we developed a supervised machine learning approach, called PPPred, for classifying the validity of a given sentence-level human protein-phenotype co-mention. In this work, we propose DeepPPPred, an ensemble classifier composed of PPPred and three deep neural network models: RNN, CNN, and BERT. Using an expanded gold-standard co-mention dataset, we demonstrate that the proposed ensemble method significantly outperforms its constituent components and provides a new state-of-the-art performance on classifying the co-mentions of human proteins and phenotype terms.
Proliferation of lung epithelial cells is regulated by the mechanisms of autophagy upon exposure of soots
Authors: Niranjan Rituraj , Mishra Kaushal Prasad , Thakur Ashwani Kumar
Published: September 2020

Soots are known to cause many diseases in humans but their underlying mechanisms of toxicity are still not known. Here, we report that, soots induce cell proliferation of lung epithelial cells via modulating autophagic pathways. Fullerene soot and diesel exhaust particles (DEP) induced cell proliferation of lung epithelial, A549 cells, via distinct autophagic mechanisms and did not cause cell death. Exposure of fullerene soot protected cell death of A549 cells, caused by hydrogen peroxide and inhibited LPS-induced autophagy. Fullerene soot co-localize with the autophagic proteins and inhibited starvation-induced autophagy (downregulated ATG-5, beclin-1, p62 and LC3 expressions) independent of its antioxidant properties. Similarly, it decreased expression profile of autophagic genes and upregulated proliferation responsive gene, Ki-67, in mice. We observed that, expressions of fullerene soot responsive genes (Beclin-1, ATG-5 and p62) were reverted by Akt Inhibitor X, indicating an important role of Akt pathway. On the other hand, DEP up-regulated expressions of autophagy genes. Akt Inhibitor X and Etoricoxib, did not attenuate DEP-induced cell proliferation and autophagic response. However, autophagic inhibiter 3-MA and chloroquine has significantly inhibited DEP-induced cell roliferation. In conclusion, distinct autophagic mechanisms are operational in cell proliferation of lung epithelial cells in response to soots and may have implication in diseases. The proliferation inducing potential of fullerene soot may be utilized as a regenerative agent in autophagy-associated disorders.
An Overview of the Application of Deep Learning in Short Read Sequence Classification
Authors: Bebris Kristaps , Polaka Inese
Published: September 2020

Advances in sequencing technology have led to an ever increasing amount of available short read sequencing data. This has, consequently, exacerbated the need for efficient and precise classification tools that can be used in the analysis of this data. As it stands, recent years have shown that massive leaps in performance can be achieved when it comes to approaches that are based in heuristics, and alongside these improvements there has been an ever increasing interest in applying deep learning techniques to revolutionize this classification task. We attempt to gather up these approaches and to evaluate their performance in a reproducible fashion to get a better perspective on the current state of deep learning based methods when it comes to the classification of short read sequencing data.
Childhood location correlates with epigenetic age and methylation stability in British-Bangladeshi migrants
Authors: Stöger Reinhard , Choi Minseung , Leeman Gregory , Emes Richard D. , Begum Khurshida , Melamed Philippa , Bentley Gillian R.
Published: September 2020

Background

Migration from one environment to another often causes marked changes in developmental conditions. Here we compare epigenetic ageing and stability of the epigenetic maintenance system among British-Bangladeshi women who grew up in Bangladesh (adult migrants), where there are higher pathogen loads and poorer health care, to second-generation Bangladeshis who grew up in the UK. In our previous studies of these migrants, those who spent their childhoods in Bangladesh also had lower levels of reproductive hormones and a shorter reproductive lifespan compared to those who grew up in the UK, suggesting life history trade-offs during development. In the present study, we hypothesised that women who grew up in Bangladesh would havei)an older epigenetic/biological age compared to the women with a childhood in the UK andii)that differences in the pace of epigenetic ageing might also be reflected by altered stability of DNA methylation marks.

Results

Illumina EPIC array methylation data from buccal tissue was used to establish epigenetic age estimates from 15 adult migrants and 11 second-generation migrants, aged 18-35 years. Using residuals from linear regression of DNA methylation-based biological age (DNAm age) on the chronological age, the results showed significant differences (p=0.016) in epigenetic age estimates: women whose childhood was in Bangladesh are on average 6.02 (± 2.34) years older, than those who grew up in London. We further investigated the efficiency of the epigenetic maintenance system which purportedly is reflected by epigenetic clocks. Methylation states of CpGs at theLHCGR/LHRlocus, which contributes to Horvath’s multi tissue epigenetic clock were evaluated. Based on the Ratio of Concordance Preference (RCP) approach that uses double-stranded methylation data, we find that maintenance of epigenetic information is more stable in women who grew up in Bangladesh.

Conclusions

The work supports earlier findings that adverse childhood environments lead to phenotypic life history trade-offs. The data indicate that childhood environments can induce subtle changes to the epigenetic maintenance system that are detectable long after exposure occurred. The implication of such a finding warrants further investigation as it implies that a less flexible epigenetic memory system established early in life could reduce the capacity to respond to different environmental conditions in adult life.
Auditory Target Detection Enhances Visual Processing and Hippocampal Functional Connectivity
Authors: Moyal Roy , Turker Hamid B. , Luh Wen-Ming , Swallow Khena M.
Published: September 2020

Though dividing one’s attention between two input streams typically impairs performance, detecting a behaviorally relevant stimulus can sometimes enhance the encoding of unrelated information presented at the same time. Previous research has shown that selection of this kind boosts visual cortical activity and memory for concurrent items. An important unanswered question is whether such effects are reflected in processing quality and functional connectivity in visual regions and in the hippocampus. In this fMRI study, participants were asked to memorize a stream of naturalistic images and press a button only when they heard a predefined target tone (400 or 1200 Hz, counterbalanced). Images could be presented with a target tone, with a distractor tone, or without a tone. Auditory target detection increased activity throughout the ventral visual cortex but lowered it in the hippocampus. Enhancements in functional connectivity between the ventral visual cortex and the hippocampus were also observed following auditory targets. Multi-voxel pattern classification of image category was more accurate on target tone trials than on distractor and no tone trials in the fusiform gyrus and parahippocampal gyrus. This effect was stronger in visual cortical clusters whose activity was more correlated with the hippocampus on target tone than on distractor tone trials. In agreement with accounts suggesting that subcortical noradrenergic influences play a role in the attentional boost effect, auditory target detection also caused an increase in locus coeruleus activity and phasic pupil responses. These findings outline a network of cortical and subcortical regions that are involved in the selection and processing of information presented at behaviorally relevant moments.
Gaining confidence in inferred networks
Authors: Diaz Léo P.M. , Stumpf Michael P.H.
Published: September 2020

Network inference is a notoriously challenging problem. Inferred networks are associated with high uncertainty and likely riddled with false positive and false negative interactions. Especially for biological networks we do not have good ways of judging the performance of inference methods against real networks, and instead we often rely solely on the performance against simulated data. Gaining confidence in networks inferred from real data nevertheless thus requires establishing reliable validation methods. Here, we argue that the expectation of mixing patterns in biological networks such as gene regulatory networks offers a reasonable starting point: interactions are more likely to occur between nodes with similar biological functions. We can quantify this behaviour using the assortativity coefficient, and here we show that the resulting heuristic,functional assortativity, offers a reliable and informative route for comparing different inference algorithms.
Lymph flow directs rapid neutrophil positioning in the lymph node in infection
Authors: Xue Jingna , Lin Yujia , Oo Darellynn , Zhang Jianbo , Jesus Flavia , Zardynezhad Ava , de Almeida Luiz G. N. , Young Daniel , Dufour Antoine , Liao Shan
Published: September 2020

Soon afterStaphylococcus aureus(S. aureus) skin infection, neutrophils infiltrate the LN via the high endothelial venules (HEVs) to restrain and kill the invading microbes to prevent systemic spread of microbes. In this study, we found that rapid neutrophil migration depends on lymph flow, through which inflammatory chemokines/cytokines produced in the infected tissue are transported to the LN. Without lymph flow, bacteria accumulation in the LN was insufficient to stimulate chemokine production or neutrophil migration. Oxazolone (OX)-induced skin inflammation impaired lymphatic function, and reduced chemokines in the LN after a secondary infection withS. aureus. Due to LN reconstruction and impaired conduit-mediated lymph flow, neutrophil preferentially transmigrated in HEVs located in the medullary sinus, where the HEVs remained exposed to lymph-borne chemokines. Altered neutrophil migration resulted in persistent infection in the LN. Our studies showed that lymph flow directed chemokine dispersal in the LN and ensured rapid neutrophil migration for timely immune protection in infection. The impaired lymph flow and neutrophil migration may contribute to the frequent infection in skin inflammation, such as atopic dermatitis.
Improved cortical surface reconstruction using sub-millimeter resolution MPRAGE by image denoising
Authors: Tian Qiyuan , Zaretskaya Natalia , Fan Qiuyun , Ngamsombat Chanon , Bilgic Berkin , Polimeni Jonathan R. , Huang Susie Y.
Published: September 2020

Automatic cerebral cortical surface reconstruction is a useful tool for cortical anatomy quantification, analysis and visualization. Recently, the Human Connectome Project and several studies have shown the advantages of using T1-weighted magnetic resonance (MR) images with sub-millimeter isotropic spatial resolution instead of the standard 1-millimeter isotropic resolution for improved accuracy of cortical surface positioning and thickness estimation. Nonetheless, sub-millimeter resolution images are noisy by nature and require averaging multiple repetitions to increase the signal-to-noise ratio for precisely delineating the cortical boundary. The prolonged acquisition time and potential motion artifacts pose significant barriers to the wide adoption of cortical surface reconstruction at sub-millimeter resolution for a broad range of neuroscientific and clinical applications. We address this challenge by evaluating the cortical surface reconstruction resulting from denoised single-repetition sub-millimeter T1-weighted images. We systematically characterized the effects of image denoising on empirical data acquired at 0.6 mm isotropic resolution using three classical denoising methods, including denoising convolutional neural network (DnCNN), block-matching and 4-dimensional filtering (BM4D) and adaptive optimized non-local means (AONLM). The denoised single-repetition images were found to be highly similar to 6-repetition averaged images, with a low whole-brain averaged mean absolute difference of ∼0.016, high whole-brain averaged peak signal-to-noise ratio of ∼33.5 dB and structural similarity index of 0.92, and minimal gray matter–white matter contrast loss (2% to 9%). The whole-brain mean absolute discrepancies in gray–white surface placement, gray–CSF surface placement and cortical thickness estimation were lower than 165 μm, 155 μm and 145 μm—sufficiently accurate for most applications. The denoising performance is equivalent to averaging ∼2.5 repetitions of the data in terms of image similarity, and 1.6–2.2 repetitions in terms of the cortical surface placement accuracy. The scan-rescan precision of the cortical surface positioning and thickness estimation was lower than 170 μm. Our unique dataset and systematic characterization support the use of denoising methods for improved cortical surface reconstruction sub-millimeter resolution.
Identifying Cancer-Relevant Mutations in the DLC START Domain using Evolutionary and Structure-Function Analyses
Authors: Holub Ashton S. , Bouley Renee A. , Petreaca Ruben C. , Husbands Aman Y.
Published: September 2020

Rho GTPase signaling promotes proliferation, invasion, and metastasis in a broad spectrum of cancers. Rho GTPase activity is regulated by the Deleted in Liver Cancer (DLC) family of bonafide tumor suppressors which directly inactivate Rho GTPases by stimulating GTP hydrolysis. In addition to a RhoGAP domain, DLC proteins contain a StAR-related lipid transfer (START) domain. START domains in other organisms bind hydrophobic small molecules and can regulate interacting partners or co-occurring domains through a variety of mechanisms. In the case of DLC proteins, their START domain appears to contribute to tumor suppressive activity. However, the nature of this START-directed mechanism, as well as the identities of relevant functional residues, remain virtually unknown. Using the Catalogue of Somatic Mutations in Cancer (COSMIC) dataset, and evolutionary and structure-function analyses, we identify several conserved residues likely to be required for START-directed regulation of DLC-1 and DLC-2 tumor suppressive capability. This pan-cancer analysis shows that conserved residues of both START domains are highly-overrepresented in cancer cells from a wide range tissues. Interestingly, in DLC-1 and DLC-2, three of these residues form multiple interactions at the tertiary structural level. Further, mutation of any of these residues is predicted to disrupt interactions and thus destabilize the START domain. As such, these mutations would not have emerged from traditional hotspot scans of COSMIC. We propose that evolutionary and structure-function analyses are an underutilized strategy which could be used to unmask cancer-relevant mutations within COSMIC. Our data also suggest DLC-1 and DLC-2 as high- priority candidates for development of novel therapeutics targeting their START domain.

Simple Summary

Deleted in Liver Cancer (DLC) proteins are tumor suppressors that contain a StAR-related lipid transfer (START) domain. Little is known about the DLC START domain including the residues that mediate its activation. Using the Catalogue of Somatic Mutations in Cancer (COSMIC) dataset, evolutionary, and structure-function analyses, we identify key functional residues of DLC START domains. Mutations in these residues are significantly overrepresented in numerous cancers in multiple tissue types. In other contexts, START domains bind hydrophobic small molecules and stimulate regulatory outputs of interacting partners or co-occurring domains. The identification of functional residues in the DLC START domain may thus have implications for targeted manipulation of DLC tumor suppressive activity. Critically, these residues would not have been identified using traditional queries of COSMIC. Thus, we propose tandem evolutionary and structure-function approaches are an underutilized strategy to unmask cancer-relevant mutations within COSMIC.
Competition for MCM Loading at Origins Establishes Replication Timing Patterns
Authors: Dukaj Livio , Rhind Nicholas
Published: September 2020

Loading of the MCM replicative helicase onto origins of replication is a highly regulated process that precedes DNA replication in all eukaryotes. The number of MCM loaded on origins has been proposed to be a key determinant of when those origins initiate replication during S phase. Nevertheless, the genome-wide characteristics of MCM loading and their direct effect on replication timing remain unclear. In order to probe MCM loading dynamics and its effect on replication timing, we perturbed MCM levels in budding yeast cells and, for the first time, directly measured MCM levels and replication timing in the same experiment. Reduction of MCM levels through degradation of Mcm4, one of the six obligate components of the MCM complex, slowed progression through S phase and increased sensitivity to replication stress. Reduction of MCM levels also led to differential loading at origins during G1, revealing origins that are sensitive to reductions in MCM and others that are not. Sensitive origins loaded less MCM under normal conditions and correlated with a weak ability to recruit the origin recognition complex (ORC). Moreover, reduction of MCM loading at specific origins of replication led to a delay in their initiation during S phase. In contrast, overexpression of MCM had no effects on cell cycle progression, relative MCM levels at origins, or replication timing, suggesting that, under optimal growth conditions, cellular MCM levels not limiting for MCM loading. Our results support a model in which the loading activity of origins, controlled by their ability to recruit ORC and compete for MCM, determines the number of helicases loaded, which in turn affects replication timing.
Telmisartan potentiates insulin secretion via ion channels, independent of the AT1 receptor and PPARγ
Authors: Liu Tao , Cui Lijuan , Xue Huan , Zhi Linping , Yang Xiaohua , Yang Huanhuan , Liu Mengmeng , Bai Tao , Liu Zhihong , Zhang Min , Guo Qing , He Peifeng , Liu Yunfeng , Zhang Yi
Published: September 2020

Angiotensin II type 1 receptor blockers (ARBs), as antihypertensive drugs, have drawn attention for their benefits to individuals with diabetes and prediabetes. However, the effects of ARBs on insulin secretion remain unclear. Here, we investigated the insulinotropic effects of ARBs (telmisartan, valsartan, and irbesartan) and the underlying electrophysiological mechanism in rat islets. We found that only telmisartan among the three ARBs exhibited an insulin secretagogue role. Distinct from other ARBs, telmisartan exerted effects on ion channels including voltage-gated potassium (Kv) channels and voltage-gated Ca2+channels to promote extracellular Ca2+influx, thereby potentiating insulin secretion in a glucose-dependent manner. We observed that the peroxisome proliferator-activated receptor γ pathway was not involved in these telmisartan-induced effects. Furthermore, we identified that telmisartan at least directly inhibited Kv2.1 channel through construction of a Chinese hamster ovary cell line with Kv2.1 channel overexpression. Acute exposure of type 2 diabetes model (db/db) mice to a telmisartan dose equivalent to therapeutic doses in humans resulted in lower blood glucose and increased plasma insulin concentration in the oral glucose tolerance test. We further observed the telmisartan-induced insulinotropic and electrophysiological effects on pathological pancreatic islets isolated fromdb/dbmice. Collectively, our results establish an important function of telmisartan distinct from other ARBs in the treatment of diabetes.
Dorsal Anterior Cingulate Cortex Encodes the Integrated Incentive Motivational Value of Cognitive Task Performance
Authors: Yee Debbie M. , Crawford Jennifer L. , Lamichhane Bidhan , Braver Todd S.
Published: September 2020

Humans can seamlessly combine value signals from diverse motivational incentives, yet it is not well-understood how these signals are “bundled” in the brain to modulate cognitive control. The dorsal anterior cingulate cortex (dACC) is theorized to integrate motivational value dimensions in the service of goal-directed action, though this hypothesis has yet to receive rigorous confirmation. In the present study, we examined the role of human dACC in motivational incentive integration. Healthy young adult men and women were scanned with fMRI while engaged in an experimental paradigm that quantifies the combined effects of liquid (e.g., juice, neutral, saltwater) and monetary incentives on cognitive task performance. Monetary incentives modulated trial-by-trial dACC activation, whereas block-related effects of liquid incentives on dACC activity were observed. When bundled together, incentive-related dACC modulation predicted fluctuations in both cognitive performance and self-report motivation ratings. Statistical mediation analyses suggest that dACC encoded the incentives in terms of their integrated subjective motivational value, and that this value signal was most proximally associated with task performance. Finally, we confirmed that these incentive integration effects were selectively present in dACC. Together, the results support an account in which dACC integrates motivational signals to compute the expected value of goal-directed cognitive control.

Significance Statement

How are primary and secondary incentives integrated in the brain to influence goal-directed behavior? Using an innovative experimental fMRI paradigm that combines motivational incentives that have historically been studied independently between species (e.g., monetary rewards for humans, food rewards for animals), we examine the relationship between incentive motivational value and cognitive control allocation. We find evidence that the integrated incentive motivational value of combined incentives is encoded in human dorsal anterior cingulate cortex (dACC). Further, self-reported motivational shifts mediated the effects of incentive-modulated dACC activity on task performance, revealing convergence in how self-reported and experimentally-induced motivation are encoded in the human brain. Our findings may inform future translational studies examining affective/motivational and cognitive impairments in psychopathology (e.g., anxiety, depression, addiction).
Statistical profiling reveals correlations between the cell response to and structural sequence of Rho-GAPs
Authors: Kang Na , Matsui Tsubasa S. , Deguchi Shinji
Published: September 2020

Rho-GTPase-activating proteins (Rho-GAPs) are essential upstream regulators of the Rho family of GTPases. Currently, it remains unclear if the phenotypic change caused by perturbations to a Rho-GAP is predictable from its structural sequence. Here we analyze the relationship between the morphological response of cells to the silencing of Rho-GAPs and their primary structure. For all possible pairs of 57 different Rho-GAPs expressed in MCF10A epithelial cells, the similarity in the Rho-GAP silencing-induced morphological change was quantified and compared to the similarity in the primary structure of the corresponding pairs. We found a distinct correlation between the morphological and structural similarities in a specific group of RhoA-targeting Rho-GAPs. Thus, the family-wide analysis revealed a common feature shared by the specific Rho-GAPs.
Utilizing emotion scores for improving classifier performance for predicting customer's intended ratings from social media posts
Authors: Ray Arghya , Bala Pradip Kumar , Jain Rashmi
Published: September 2020

Purpose

Social media channels provide an avenue for expressing views about different services/products. However, unlike merchandise/company websites (where users can post both reviews and ratings), it is not possible to understand user's ratings for a particular service-related comment on social media unless explicitly mentioned. Predicting ratings can be beneficial for service providers and prospective customers. Additionally, predicting ratings from a user-generated content can help in developing vast data sets for recommender systems utilizing recent data. The aim of this study is to predict ratings more accurately and enhance the performance of sentiment-based predictors by combining it with the emotional content of textual data.

Design/methodology/approach

This study had utilized a combination of sentiment and emotion scores to predict the ratings of Twitter posts (3,509 tweets) in three different contexts, namely, online food delivery (OFD) services, online travel agencies (OTAs) and online learning (e-learning). A total of 29,551 reviews were utilized for training and testing purposes.

Findings

Results of this study indicate accuracies of 58.34%, 57.84% and 100% in cases of e-learning, OTA and OFD services, respectively. The combination of sentiment and emotion scores showed an increase in accuracies of 19.41%, 27.83% and 40.20% in cases of e-learning, OFD and OTA services, respectively.

Practical implications

Understanding the ratings of social media comments can help both service providers as well as prospective customers who do not spend much time reading posts but want to understand the perspectives of others about a particular service/product. Additionally, predicting ratings of social media comments will help to build databases for recommender systems in different contexts.

Originality/value

The uniqueness of this study is in utilizing a combination of sentiment and emotion scores to predict the ratings of tweets related to different online services, namely, e-learning OFD and OTAs.
Convective fluid flow and heat transfer in a vertical rectangular duct containing a horizontal porous medium and fluid layer
Authors: Umavathi J.C. , Anwar Beg O.
Published: September 2020

Purpose

The purpose of this paper is to investigate thermally and hydrodynamically fully developed convection in a duct of rectangular cross-section containing a porous medium and fluid layer.

Design/methodology/approach

The Darcy–Brinkman–Forchheimer flow model is adopted. A finite difference method of second-order accuracy with the Southwell-over-relaxation method is deployed to solve the non-dimensional momentum and energy conservation equations under physically robust boundary conditions.

Findings

It is found that the presence of porous structure and different immiscible fluids exert a significant impact on controlling the flow. Graphical results for the influence of the governing parameters i.e. Grashof number, Darcy number, porous media inertia parameter, Brinkman number and ratios of viscosities, thermal expansion and thermal conductivity parameters on the velocity and temperature fields are presented. The volumetric flow rate, skin friction and rate of heat transfer at the left and right walls of the duct are also provided in tabular form. The numerical solutions obtained are validated with the published study and excellent agreement is attained.

Originality/value

To the author’s best knowledge this study original in developing the numerical code using FORTRAN to assess the fluid properties for immiscible fluids. The study is relevant to geothermal energy systems, thermal insulation systems, resin flow modeling for liquid composite molding processes and hybrid solar collectors.
The fierce urgency of now and forever and unto ages of ages: study and the restoration of paradise on Earth
Authors: Wilson Simon
Published: September 2020

Purpose

The purpose of this paper is to explore and evoke an old educational concept called “study”. This is learning which leads to love and love which leads to learning. It is a dynamic experience which engenders transformation whose telos is simultaneously endlessly knowable and unknowable. The paper argues that it unites humans with the world, the material world with the transcendent, speed with slowness and alignment with resistance, in a series of antinomic relationships which come together in the heart. Study, it is argued, should form the basis of true education and a truly sustainable relationship with the world.

Design/methodology/approach

The paper’s approach is informed by the Eastern Orthodox Christian theology of ecology, particularly its complex and holistic concept of the heart and perceiving with the heart. It revels in the antinomies fostered by this tradition.

Findings

The paper’s findings are inevitably provisional. They stress the need for beauty in educational practice and indicate that the form of study described may foster an individual sense of vocation, which can transform self and the world.

Originality/value

The paper hopes to contribute to a re-orientation in education, sustainability and ecology.
Learning motivational interviewing: prospects to preserve practitioners' well-being
Authors: Endrejat Paul C. , Kauffeld Simone
Published: September 2020

Purpose

Motivational interviewing (MI) is a collaborative communication style designed to help clients achieve desired behavior changes. MI includes communication methods along with a mindset that avoids attempting to impose behavior change. Relying on the conservation of resources theory, this research report argues that learning MI helps practitioners communicate more effectively and preserve their own psychological health resources.

Design/methodology/approach

We tested whether MI training resulted in beneficial effects on practitioners' resilience and burnout (i.e. exhaustion and disengagement), surveying participants (N = 42) from various disciplines who learned MI at a training institute. Subjects received a questionnaire before and one month after MI training. The post-training questionnaire also assessed whether participants applied the training content in practice.

Findings

The results revealed that the training reduced participants' disengagement. Practical application was a predictor for this decrease as well as an increase in resilience.

Research limitations/implications

Due to the small sample size and self-reported data, this paper should be considered an experimental study that could inspire future research in this area, using more elaborate research designs.

Practical implications

Learning MI not only helps in facilitating behavior change in clients but also in bolstering practitioners' own resources. MI novices should aim to apply their newly acquired skills.

Originality/value

This study is among the first to explicitly hint at the possibility that learning MI helps practitioners preserve their psychological resources.
The team as a secure base revisited: remote working and resilience among child and family social workers during COVID-19
Authors: Cook Laura Louise , Zschomler Danny , Biggart Laura , Carder Sara
Published: September 2020

Purpose

Social work teams can provide a secure base for social workers, supporting them to manage the emotional demands of child and family social work (Biggart et al., 2017). As the COVID-19 pandemic has necessitated increased remote working, social workers have needed to maximise their use of virtual networks and navigate new ways of connecting with colleagues. This study aims to examine the extent to which social work teams can function as a secure base in the context of remote working.

Design/methodology/approach

Between 19th March and 13th June, the authors undertook 31 in-depth, qualitative interviews with child and family social workers across 9 local authorities in England. this research captured social workers’ perspectives on remote working and team support throughout lockdown in England.

Findings

In this study, the authors report findings in three key areas: how social workers experienced the sudden shift to increased remote working; how social work teams provided a secure base for remote working; and the challenges for sustaining the team as a secure base when working remotely.

Originality/value

These findings will be of interest to social workers, managers and local authorities as they adapt to the challenges of increased remote working in child and family social work.
Is the investment decision affected by the independence and competence of the audit committee? A comparative study between Bahrain and Indonesia
Authors: Al-Hadrami Abdullah Hamza , Rafiki Ahmad , Sarea Adel , Nasution Muhammad Dharma Tuah Putra
Published: September 2020

Purpose

This study aims to investigate the impact of the audit committee’s (AC’s) independence and competence in the company’s investment decision-making in Bahraini- and Indonesian-listed firms, then to compare the two results

Design/methodology/approach

A quantitative method is used and cross-sectional data are collected through a self-administered questionnaire survey. A stratified random sample technique is adopted with a total of 409 respondents from 39 listed companies in Bahrain and 303 respondents from 27 companies listed on the Indonesia Stock Exchange (IDX). A descriptive analysis is used to identify the characteristics of the respondents, while a correlation analysis, linear regression and t-test analyses are used to test the model, explain the relationships among variables and compare the two studies (Bahrain vs Indonesia).

Findings

It is found that the AC independence and AC competence have a positive and significant influence on investment decision-making for both the Bahrain and the Indonesia studies

Practical implications

The current study’s results have implications for the process of appointing and nominating the AC members, since this would affect an investor’s investment decision. Investors’ perception of the independence and competence of ACs will make a difference in their investment decisions.

Originality/value

AC independence and competence are importantly crucial for the decision-makers in improving the quality of financial reporting, internal control, and audit. This may lead to an increase in investors’ trust in financial reports and their ability to make favorable investment decisions.
Measuring financial literacy: a literature review
Authors: Ouachani Sonia , Belhassine Olfa , Kammoun Aïda
Published: September 2020

Purpose

The purpose of this paper is to review the main methods used in the literature to measure financial literacy (FL) of individuals.

Design/methodology/approach

The paper begins by describing how the different items used to measure the FL level of individuals are constructed. Then, it focuses on how do researchers select the items. Finally, it reviews the different calculation methods used in the literature to assess the FL level.

Findings

FL as a concept is tough to define and measure. Several studies focus on the definition and the measure of this concept. Different items are used in the literature and are mostly related to the study topics. The used calculation methods differ across the different studies.

Originality/value

This paper sheds light on the principal methodologies used in the literature to measure FL. It highlights the relationship between the items' content areas and the studies' subjects. Thus, this paper suggests guidance for future studies on measuring methods of FL.