bluuebunny/crossref_metadata_2025_split huggingface dataset:
Deep Learning Predicts Patterns of Cardiotoxicity in a High-Content Screen Using Induced Pluripotent Stem Cell–Derived Cardiomyocytes
Authors: Grafton Francis , Ho Jaclyn , Ranjbarvaziri Sara , Farshidfar Farshad , Budan Ana , Steltzer Stephanie , Maddah Mahnaz , Loewke Kevin E. , Green Kristina , Patel Snahel , Hoey Tim , Mandegar Mohammad A. 
Published: March 2021

ABSTRACTDrug-induced cardiotoxicity and hepatotoxicity are major causes of drug attrition. To decrease late-stage drug attrition, pharmaceutical and biotechnology industries need to establish biologically relevant models that use phenotypic screening to predict drug-induced toxicity. In this study, we sought to rapidly detect patterns of cardiotoxicity using high-content image analysis with deep learning and induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs). We screened a library of 1280 bioactive compounds and identified those predicted to have cardiotoxic liabilities using a single-parameter score based on deep learning. Compounds with major predicted cardiotoxicity included DNA intercalators, ion channel blockers, epidermal growth factor receptor, cyclin-dependent kinase, and multi-kinase inhibitors. We also screened a diverse library of molecules with unknown targets and identified chemical frameworks with predicted cardiotoxic liabilities. By using this screening approach during target discovery and lead optimization, we can de-risk early-stage drug discovery. We show that the broad applicability of combining deep learning with iPSC technology is an effective way to interrogate cellular phenotypes and identify drugs that protect against diseased phenotypes and deleterious mutations.GRAPHICAL ABSTRACTCONTRIBUTION TO THE FIELDIn this article, Grafton and colleagues use induced pluripotent stem cell technology and deep learning to train a neural network capable of detecting patterns of cardiotoxicity. To identify bioactive and chemical classes that lead to cardiotoxicity, they combine the neural network with high-content screening of 2560 compounds. The methods described in this study can be used to de-risk early-stage drug development, triage hits, and identify drugs that protect against disease. This screening paradigm will serve as a useful resource for drug discovery and phenotypic interrogation of stem cells and stem cell–derived cell types.
Viability markers for determination of desiccation tolerance and critical stages during dehydration inSelaginellaspecies
Authors: Alejo-Jacuinde Gerardo , Kean-Galeno Tania , Martínez-Gallardo Norma , Tejero-Díez J. Daniel , Mehltreter Klaus , Délano-Frier John P. , Oliver Melvin J. , Simpson June , Herrera-Estrella Luis 
Published: March 2021

AbstractPlants can tolerate some degree of dehydration but below a threshold of water content most plants die. However, some species display specific physiological, biochemical, and molecular responses that allow survival to desiccation. Some of these responses are activated at critical stages during water loss and could represent the difference between desiccation tolerance (DT) and death. Here, we report the development of a simple and reproducible system to determine DT inSelaginellaspecies. This system is based on the use of excised tissue (explants), exposed to a dehydration agent inside small containers, rather than whole plants making it faster, better controlled, and potential use under field conditions. We also report that the triphenyltetrazolium chloride test is a simple and accurate assay to determine tissue viability. The explant system is particularly useful to identify critical points during the dehydration process and was applied to identify novel desiccation-tolerantSelaginellaspecies. Our data suggest that desiccation-sensitiveSelaginellaspecies have a change in viability when dehydrated to 40% RWC, indicating the onset of a critical condition at this water content. Comparative studies at these critical stages could provide a better understanding of DT mechanisms and unravel insights into the key responses to survive desiccation.HighlightIn this article, we developed a simple and efficient system to determine desiccation tolerance and critical stages during the dehydration process inSelaginellathat can be applied to other plant species.
β-arrestin-mediated Angiotensin II type 1 Receptor Activation Promotes Pulmonary Vascular Remodeling in Pulmonary Hypertension
Authors: Ma Zhiyuan , Viswanathan Gayathri , Sellig Mason , Jassal Chanpreet , Choi Issac , Xiong Xinyu , Nazo Nour , Rajagopal Sudarshan 
Published: March 2021

AbstractObjectivesThe goal of this study was to test whether a β-arrestin-biased agonist of the angiotensin II (AngII) type 1 receptor (AT1R), which acts as a vasodilator while not blocking cellular proliferation, would have positive effects compared to a balanced agonist, angiotensin II (AngII), or an antagonist, losartan, in pulmonary arterial hypertension (PAH).BackgroundPAH is a disease of abnormal pulmonary vascular remodeling whose treatment has focused on targeting vasoactive substances, such as inhibiting endothelin signaling and promoting prostacyclin signaling. PAH medical therapies are thought to primarily act as vasodilators, although they may also have effects on pulmonary vascular remodeling. There are a number of reports that blocking AT1R signaling can be beneficial in preclinical models of PAH. The AT1R is a G protein-coupled receptor (GPCR) that promotes vasoconstriction through heterotrimeric G proteins but also signals via β-arrestins, which promote cardioprotective effects and vasodilation.MethodsWe compared the effects of a β-arrestin-biased AT1R agonist, TRV120023 (TRV023), to a balanced agonist (AngII) and an antagonist (losartan) in preclinical PAH models.ResultsIn acute infusion studies, AngII increased right ventricular (RV) pressures while TRV023 did not. However, with chronic infusion in monocrotaline (MCT) PAH rats, TRV023 failed to improve hemodynamics or survival compared to AngII, while losartan significantly improved survival. Both TRV023 and AngII enhanced proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) from PAH patients, which was associated with the promotion of proliferative MAP kinase signaling.Conclusionsβ-arrestin-mediated AT1R signaling promotes vascular remodeling and worsens PAH, and suggests that the primary benefit of current PAH therapies is through pulmonary vascular reverse remodeling and not vasodilation.
Mast cell function in prostate inflammation, fibrosis, and smooth muscle cell dysfunction
Authors: Pattabiraman Goutham , Bell-Cohn Ashlee J. , Murphy Stephen F. , Mazur Daniel J. , Schaeffer Anthony J. , Thumbikat Praveen 
Published: March 2021

ABSTRACTIntraurethral inoculation of mice with uropathogenicE. coli(CP1) results in prostate inflammation, fibrosis, and urinary dysfunction, recapitulating some but not all of the pathognomonic clinical features associated with benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS). In both patients with LUTS and in CP1-infected mice, we observed increased numbers and activation of mast cells and elevated levels of prostate fibrosis. Therapeutic inhibition of mast cells and the histamine 1 receptor in the mouse model resulted in reduced mast cell activation in the prostate and significant alleviation of urinary dysfunction. Treated mice showed reduced prostate fibrosis, less infiltration of immune cells, and decreased inflammation. In addition, as opposed to symptomatic CP1-infected mice, treated mice showed reduced myosin light chain (MLC)-2 phosphorylation, a marker of prostate smooth muscle contraction. These results show that mast cells play a critical role in the pathophysiology of urinary dysfunction and may be an important therapeutic target for men with BPH/LUTS.NEW AND NOTEWORTHYLUTS-associated BPH is derived from a combination of immune activation, extracellular matrix remodeling, hyperplasia, and smooth muscle cell contraction in prostates of men. Using a mouse model, we describe the importance of mast cells in regulating these multiple facets involved in the pathophysiology of LUTS. Mast cell inhibition alleviates both pathology and urinary dysfunction in this model suggesting the potential for mast cell inhibition as a therapeutic that prevents and reverses pathology and associated symptomology.
Insular cortex corticotropin-releasing factor integrates stress signaling with social decision making
Authors: Rieger Nathaniel S. , Varela Juan A. , Ng Alexandra , Granata Lauren , Djerdjaj Anthony , Brenhouse Heather C. , Christianson John P. 
Published: March 2021

AbstractImpairments in social cognition manifest in a variety of psychiatric disorders, making the neurobiological mechanisms underlying social decision making of particular translational importance. The insular cortex is consistently implicated in stress-related social and anxiety disorders, which are associated with diminished ability to make and use inferences about the emotions of others to guide behavior. We investigated how corticotropin releasing factor (CRF), a neuromodulator evoked by both self and social stressors, influenced the insula. In acute slices from male and female rats, CRF depolarized insular pyramidal neurons. In males, but not females, CRF suppressed presynaptic GABAergic inhibition leading to greater excitatory synaptic efficacy in a CRF receptor 1 (CRF1) and cannabinoid receptor 1 (CB1) dependent fashion. In males only, insular CRF increased social investigation, and CRF1and CB1antagonists interfered with social decision making. To investigate the molecular and cellular basis for the effect of CRF we examined insular CRF1and CB1mRNAs and found greater total insula CRF1mRNA in females but greater CRF1and CB1mRNA colocalization in male insular cortex glutamatergic neurons which suggest complex, sex-specific organization of CRF and endocannabinoid systems. Together these results reveal a new sex-specific mechanism by which stress and affect contribute to social decision making.
Untangling the cell immune response dynamic for severe and critical cases of SARS-CoV-2 infection
Authors: Blanco-Rodríguez Rodolfo , Du Xin , Hernández-Vargas Esteban 
Published: March 2021

ABSTRACTCOVID-19 is a global pandemic leading high death tolls worldwide day by day. Clinical evidence suggests that COVID-19 patients can be classified as non-severe, severe and critical cases. In particular, studies have highlighted the relationship between the lymphopenia and the severity of the illness, where CD8+T cells have the lowest levels in critical cases. In this work, we aim to elucidate the key parameters that define the course of the disease deviating from severe to critical case. To this end, several mathematical models are proposed to represent the dynamic of the immune response in patients with SARS-CoV-2 infection. The best model had a good fit to reported experimental data, and in accordance with values found in the literature. Our results suggest that a rapid proliferation of CD8+T cells is decisive in the severity of the disease.
Proteasome homeostasis is essential for a robust cauliflower mosaic virus infection
Authors: Shukla Aayushi , Ustun Suayib , Hafrén Anders 
Published: March 2021

SummaryThe ubiquitin-proteasome system (UPS) is essential for the maintenance and shifts in protein homeostasis, and thereby forms a founding pillar in virtually all cellular processes including plant immunity and viral infections. According to its importance in fine-tuning the complex plant immune response, proteasomal defects result in divergent outcomes including both resistance and susceptibility phenotypes in response to viruses. The final outcome will largely depend on the specific virus and its specific co-adaptation with the UPS as well as the immune system. Here, we show that cauliflower mosaic virus (CaMV) relies on the proteasome for robust infection. The proteasome system is induced during infection via SA and supports systemic accumulation of the virus as well as plant growth performance during infection. This establishes the UPS as a win-win pathway for the plant and the virus, and together with our demonstration of a proteasome-suppressing viral effector, the intimacy between the proteasome and CaMV is fortified.
Translocation of chloroplast NPR1 to the nucleus in retrograde signaling for adaptive response to salt stress in tobacco
Authors: Seo So Yeon , Park Ky Young 
Published: March 2021

AbstractChloroplasts play a pivotal role in biotic and abiotic stress responses, accompanying changes in the cell reduction/oxidation (redox) state. Chloroplasts are an endosymbiotic organelle that sends retrograde signals to the nucleus to integrate with environmental changes. This study showed that salt stress causes the rapid accumulation of the nonexpressor of pathogenesis-related genes 1 (NPR1) protein, a redox-sensitive transcription coactivator that elicits many tolerance responses in chloroplasts and the nucleus. The transiently accumulated chloroplast NPR1 protein was translocated to the nucleus in a redox-dependent manner under salinity stress. In addition, immunoblotting and fluorescence image analysis showed that chloroplast-targeted NPR1-GFP fused with cTP (chloroplast transit peptide from RbcS) was localized in the nucleus during the responses to salt stress. Chloroplast functionality was essential for retrograde translocation, in which the stomules and cytoplasmic vesicles participated. Treatments with H2O2and an ethylene precursor enhanced this retrograde translocation. Compared to each wild-type plant, retrograde signaling-related gene expression was severely impaired in thenpr1-1mutant in Arabidopsis, but enhanced transiently in theNPR1-Oxtransgenic tobacco line. Therefore, NPR1 might be a retrograde signaling hub that improves a plant’s adaptability to changing environments.
Ezh2 mediates epigenetic regulation of osteoclastogenesis and bone remodeling in mice
Authors: Chen Jin-Ran , Lazarenko Oxana P. , Gai Dongzheng , Li Can , Blackburn Michael L. , Zhan Fenghuang 
Published: March 2021

ABSTRACTOsteoclasts derived from hematopoietic stem cells control bone resorption. Identifying novel molecules that can epigenetically regulate osteoclastogenesis has been an important basic and clinical issue. The polycomb group (PcG) protein enhancer of zeste homologue 2 (Ezh2), a histone lysine methyltransferase is associated with epigenetic regulation of numerous cellular processes, it is not yet clear on its involvement in bone cell development and homeostasis. Here, we crossed LysM-Cre mice with Ezh2flox/floxmice to delete Ezh2 in myeloid cell lineage mature macrophages. Conditional deletion of Ezh2 in macrophages resulted in significant increases in postnatal bone growth in the first 6 months of life, but tibia length and body weight gains were not different in knockout mice compared with their wild type controls. Significantly decreased osteoclastogenesis but increased bone mass without osteopetrosis were found in Ezh2 conditional knockout (CKO) mice. In contrast to female mice, one floxed Ezh2 gene copy recombinant with LysM-Cre+(Ezh2flox/+LysM-Cre+) produced increased bone mass in young adult male mice compared with control mice (Ezh2flox/flox, LysM-Cre+and wild type). Inflammatory milieu in bone was significantly lower in both male and female CKO mice compared with their respective controls. Deletion of Ezh2 in macrophages triggered increased gene expression of osteoclast suppressors, IRF8, MafB and Arg1 due to decreased Ezh2-induced trimethylation of H3K27me3. Conversely, NFATc1 and Cathepsin k expression were decreased. These findings suggest that pre-osteoclastic cell differentiation is under epigenetic control of osteoclast suppressive gene expression via an Ezh2-dependent mechanisms.
Microenvironment evolution and SCC behavior of subsea pipeline within disbonded coating crevice in a seawater environment under cathodic protection
Authors: Zhang Wei , Liu Hongqun , Hu Minglei , Wu Wei 
Published: March 2021

Purpose
This paper aims to make clear the sensitive zone of subsea pipeline to stress corrosion cracking (SCC) under a disbonded coating.

Design/methodology/approach
The change of microenvironment under a disbonded coating in artificial seawater was analyzed by using a rectangular crevice cell. The SCC behavior of subsea pipeline was studied by slow strain rate tensile tests.

Findings
The microenvironment at the crevice bottom exhibits obvious acidification, Cl- aggregation and cathodic protection potential (CP) rise. Accordingly, the susceptibility of X70 steels to SCC is high due to the intensive anodic dissolution effect. At the opening, hydrogen atom can access into the steel and induce hydrogen embrittlement effect on account of the applied over-protected CP potential, resulting in a relatively high susceptibility to SCC. The corrosiveness of the microenvironment at crevice middle, however, is mild with proper CP potential; thus, the susceptibility of X70 steel to SCC here is lower than that obtained at the opening and the crevice bottom.

Originality/value
A rectangular crevice cell is built to survey the microenvironment evolution under a disbonded coating in situ. The sensitive zone of subsea pipeline to SCC under a disbonded coating is clarified.
Family firm CEOs: human capital and career success
Authors: Blanco Maria Rita , Sastre-Castillo Miguel Angel , Montoro-Sanchez Maria Angeles 
Published: March 2021

PurposeThis article explores the influence of education and experience on the time to the top in family and non-family CEOs who work for Latin American family firms.Design/methodology/approachIn order to achieve these objectives, this study draws upon human capital theory as well as career and family firm literature. The careers of 129 CEOs of family firms who form part of the América Economía ranking were analyzed and quantitative methods were used.FindingsIn Latin American family firms, family CEOs reach the top faster than their non-family counterparts. In addition, the influence of human capital variables on the way to the top differs between the two groups. For family CEOs, obtaining a graduate degree delays the way to the top, while for non-family ones, it reduces the time to the top. As regards experience, for promoted family CEOs, the greater the percentage of the career spent in the organization they lead, the shorter the time to the top. No support was found for either the influence of having worked for just one firm or having had elite graduate education abroad, in multilatina CEOs.Practical implicationsIndividual career management suggestions for future CEOs as well as specific guidelines for talent managers are proposedOriginality/valueThis is the first study to explore the influence of human capital indicators on the time to the top in Latin American family firm CEOs.
How can consumer involvement be changed through communication campaigns? An information content choice model applied to the olive oil case
Authors: Garrido-Castro Elisa , Murgado-Armenteros Eva María , Torres-Ruiz Francisco José 
Published: March 2021

PurposeInvolvement has been one of the most studied variables in the field of marketing due to its determinant role in consumer behaviour, but always as a contextual or mediating variable. Taking its relationship with knowledge as the starting point, in this work, the purpose of this paper is to examine how to use the choice of information content in communication campaigns to drive up the level of involvement. A new method based on Qualitative Comparative Analysis (QCA) models is applied to the case of olive oil.Design/methodology/approachQuantitative research has been used for the proposed objectives of this work. Specifically, a computer-assisted telephone interviewing (CATI) has been conducted in several Spanish provinces using a structured questionnaire. Data obtained from 829 consumers are used.FindingsThe results support that consumer involvement with the product is related to objective knowledge about the product and its demand. Moreover, involvement can be modified through objective knowledge or information. Specifically, consumer involvement can be increased by the choice and communication of an optimal combination of five specific pieces of information (SPIs)Originality/valueIn this paper, involvement is considered as a result variable, i.e. a variable that can be modified or increased. This greater involvement can be achieved by improving the level of objective knowledge about a product. In addition, a new model is used and its viability is demonstrated and its ease of application to agri-food context.
Strategic innovation and entrepreneurial ownership: an analysis using GEM data and fuzzy simulation
Authors: Dinesh Kamala Kannan , Sushil  
Published: March 2021

PurposeThis paper aims to study entrepreneurial ownership and technological input on product innovation globally and in the Indian context. The data used in this study is collected from the Global Entrepreneurship Monitor (GEM).Design/methodology/approachThe study evaluates strategic innovation and entrepreneurial ownership in global and country-level data. The study was extracted from global and country-level data by the GEM. One of the methods used is ordinal regression analysis to examine the importance of entrepreneurial ownership and technology usage on product innovation. Another technique used is the fuzzy-based simulation to simulate the scenario of entrepreneurial ownership and usage of technology in business processes impacting product innovation.FindingsResults from statistical analysis indicate that entrepreneurial ownership is high in India compared to the globe. The usage of technology and its excellence is still lower than the global level and in other countries. In India, product innovation is achieved because of strong entrepreneurial ownership but, globally product innovation is achieved because of the higher level of technological excellence and technology usage in innovation activities. The fuzzy-based simulation shows that product innovation is at peak only when both technological input and entrepreneurial ownership are high.Originality/valueThis paper's original contribution is that the fuzzy-based simulations are applied to GEM data to study the relationships of entrepreneurial ownership and technological input on product innovation through simulation. The study has shed light on how entrepreneurial ownership and usage of technology are influential in product innovation.