bluuebunny/crossref_metadata_2025_split huggingface dataset:
A G-protein-biased S1P1 agonist, SAR247799, improved LVH and diastolic function in a rat model of metabolic syndrome
Authors: Evaristi Maria-Francesca , Poirier Bruno , Chénedé Xavier , Lefebvre Anne-Marie , Roccon Alain , Gillot Florence , Beeské Sandra , Corbier Alain , Pruniaux-Harnist Marie-Pierre , Janiak Philip , Parkar Ashfaq A. 
Published: September 2021

AbstractAimHeart failure with preserved ejection fraction (HFpEF) is a major cause of death worldwide with no approved treatment. Left ventricular hypertrophy (LVH) and diastolic dysfunction represent the structural and functional components of HFpEF, respectively. Endothelial dysfunction is prevalent in HFpEF and predicts cardiovascular events. We investigated if SAR247799, a G-protein-biased sphingosine-1-phosphate receptor 1 (S1P1) agonist with endothelial-protective properties, could improve cardiac and renal functions in a rat model of metabolic syndrome LVH and diastolic function.Methods31- and 65-week-old obese ZSF1 (Ob-ZSF1) rats, representing young and old animals with LVH and diastolic dysfunction, were randomized to a chow diet containing 0.025% (w/w) of SAR247799, or control (CTRL) chow for 4 weeks. Age-matched lean ZSF1 (Le-ZSF1) rats were fed control chow. Echocardiography, telemetry, biochemical and histological analysis were performed to evaluate the effect of SAR247799.ResultsEchocardiography revealed that Ob-ZSF1 rats, in contrast to Le-ZSF1 rats, developed progressive diastolic dysfunction and cardiac hypertrophy with age. SAR247799 blunted the progression of diastolic dysfunction in young and old animals: in young animals E/e’ was evaluated at 21.8 ± 1.4 for Ob-ZSF1-CTRL, 19.5 ± 1.2 for Ob-ZSF1-SAR247799 p<0.01, and 19.5 ± 2.3 for Le-ZSF1-CTRL (median ± IQR). In old animals E/e’ was evaluated at 23.15 ± 4.45 for Ob-ZSF1-CTRL, 19.5 ± 5 for Ob-ZSF1-SAR247799 p<0.01, and 16.69 ± 1.7 for Le-ZSF1-CTRL, p<0.01 (median ± IQR). In old animals, SAR247799 reduced cardiac hypertrophy (mean ± SEM of heart weight/tibia length 0.053 ± 0.001 for Ob-ZSF1-CTRL vs 0.046 ± 0.002 for Ob-ZSF1-SAR247799 p<0.01, Le-ZSF1-CTRL 0.035 ± 0.001) and myocardial perivascular collagen content (p<0.001), independently of any changes in microvascular density. In young animals, SAR247799 improved endothelial function as assessed by the very low frequency bands of systolic blood pressure variability (mean ± SEM 67.8 ± 3.41 for Ob-ZSF1-CTRL 55.8 ± 4.27 or Ob-ZSF1-SAR247799, p<0.05 and 57.3 ± 1.82 Le-ZSF1-CTRL), independently of any modification of arterial blood pressure. In old animals, SAR247799 reduced urinary protein/creatinine ratio, an index of glomerular injury, (10.3 ± 0.621 vs 8.17 ± 0.231 for Ob-ZSF1-CTRL vs Ob-ZSF1-SAR247799, respectively, p<0.05 and 0.294 ± 0.029 for Le-ZSF1-CTRL, mean ± SEM) and the fractional excretion of electrolytes. Circulating lymphocytes were not decreased by SAR247799, confirming lack of S1P1 desensitization.ConclusionsThese experimental findings suggest that S1P1 activation with SAR247799 could improve LVH, cardiac diastolic and renal function in HFpEF patients.
Synthetic lethality-based prediction of anti-SARS-CoV-2 targets
Authors: Pal Lipika R. , Cheng Kuoyuan , Nair Nishanth Ulhas , Martin-Sancho Laura , Sinha Sanju , Pu Yuan , Riva Laura , Yin Xin , Schischlik Fiorella , Lee Joo Sang , Chanda Sumit K. , Ruppin Eytan 
Published: September 2021

AbstractNovel strategies are needed to identify drug targets and treatments for the COVID-19 pandemic. The altered gene expression of virus-infected host cells provides an opportunity to specifically inhibit viral propagation via targeting the synthetic lethal (SL) partners of such altered host genes. Pursuing this antiviral strategy, here we comprehensively analyzed multiple in vitro and in vivo bulk and single-cell RNA-sequencing datasets of SARS-CoV-2 infection to predict clinically relevant candidate antiviral targets that are SL with altered host genes. The predicted SL-based targets are highly enriched for infected cell inhibiting genes reported in four SARS-CoV-2 CRISPR-Cas9 genome-wide genetic screens. Integrating our predictions with the results of these screens, we further selected a focused subset of 26 genes that we experimentally tested in a targeted siRNA screen using human Caco-2 cells. Notably, as predicted, knocking down these targets reduced viral replication and cell viability only under the infected condition without harming non-infected cells. Our results are made publicly available, to facilitate their in vivo testing and further validation.
Antifungal activity of fibrate-based compounds and substituted pyrroles inhibiting the enzyme 3-hydroxy-methyl-glutaryl-CoA reductase of Candida glabrata (CgHMGR), and decreasing yeast viability and ergosterol synthesis
Authors: Madrigal-Aguilar Damián A. , Gonzalez-Silva Adilene , Rosales-Acosta Blanca , Bautista-Crescencio Celia , Ortiz-Álvarez Jossué , Escalante Carlos H. , Sánchez-Navarrete Jaime , Hernández-Rodríguez César , Chamorro-Cevallos Germán , Tamariz Joaquín , Villa-Tanaca Lourdes 
Published: September 2021

ABSTRACTDue to the emergence of multi-drug resistant strains of yeasts belonging to the Candida genus, there is an urgent need to discover antifungal agents directed at alternative molecular targets. The aim of the current study was to evaluate the capacity of synthetic compounds to inhibit the Candida glabrata enzyme denominated 3-hydroxy-methyl-glutaryl-CoA reductase (CgHMGR), and thus affect ergosterol synthesis and yeast viability. One series of synthetic antifungal compounds were analogues to fibrates, a second series had substituted 1,2-dihydroquinolines and the third series included substituted pyrroles. α-asarone-related compounds 1c and 5b with a pyrrolic core were selected as the best antifungal candidates. Both inhibited the growth of fluconazole-resistant C. glabrata 43 and fluconazole-susceptible C. glabrata CBS 138. A yeast growth rescue experiment based on the addition of exogenous ergosterol showed that the compounds act by inhibiting the mevalonate synthesis pathway. A greater recovery of yeast growth occurred for the C. glabrata 43 strain and after the 1c (versus 5b) treatment. Given that the compounds decreased the ergosterol concentration in the yeast strains, they probably target the ergosterol synthesis. According to the docking analysis, the inhibitory effect of the 1c and 5b could possibly be mediated by their interaction with the amino acid residues of the catalytic site of CgHMGR. Since 1c displayed higher binding energy than α-asarone and 5b, it is a good candidate for further research, which should include structural modifications to increase its specificity and potency as well as in vivo studies on its effectiveness at a therapeutic dose.HIGHLIGHTSFibrate-based and pyrrole-containing compounds were tested as C. glabrata inhibitors.The best inhibitor from fibrate was 1c and from pyrroles was 5b.These agents inhibited C. glabrata growth better than the reference antifungals.They also inhibited ergosterol synthesis by the two C. glabrata strains tested. Experimental
In vivo serial passaging of human-simian immunodeficiency virus clones identifies viral characteristics that enhance persistent viral replication
Authors: Thippeshappa Rajesh , Polacino Patricia , Chandrasekar Shaswath S. , Truong Khanghy , Misra Anisha , Hu Shiu-Lok , Kaushal Deepak , Kimata Jason T. 
Published: September 2021

AbstractWe previously reported that a human immunodeficiency virus type 1 with a simian immunodeficiency virus vif substitution (HSIV-vifNL4-3) could replicate in pigtailed macaques (PTMs), demonstrating that Vif is a species-specific tropism factor of primate lentiviruses. However, infections did not result in high peak viremia or setpoint plasma viral loads, as observed during SIV infection of PTMs. Here, we characterized variants isolated from one of the original infected animals with CD4 depletion after nearly four years of infection to identify determinants of increased replication fitness. In our studies, we found that the HSIV-vif clones did not express the HIV-1 Vpr protein due to interference from the vpx open reading frame in singly spliced vpr mRNA. To examine whether these viral genes contribute to persistent viral replication, we generated infectious HSIV-vif clones expressing either the HIV-1 Vpr or SIV Vpx protein. And then to determine viral fitness determinants of HSIV-vif, we conducted three rounds of serial in vivo passaging in PTMs, starting with an initial inoculum containing a mixture of CXCR4-tropic (Vpr- HSIV-vifNL4-3 isolated at 196 (C/196) and 200 (C/200) weeks post-infection from a PTM with depressed CD4 counts) and CCR5-tropic HSIV (Vpr+ HSIV-vif derivatives based NL-AD8 and Bru-Yu2 and a Vpx expressing HSIV-vifYu2). Interestingly, all infected PTMs showed peak plasma viremia close to or above 105 copies/ml and persistent viral replication for more than 20 weeks. The passage 3 PTM showed peak viral loads greater than 105 viral RNA copies/ml. Infectious molecular clones (IMCs) recovered from the passage 3 PTM (HSIV-P3 IMCs) included mutations required for HIV-1 Vpr expression and those mutations encoded by the CXCR4-tropic HSIV-vifNL4-3 isolates C/196 and C/200. The data indicate that the biological isolates selected during long-term infection acquired HIV-1 Vpr expression to enhance their replication fitness in PTMs. Further passaging of HSIV-P3 IMCs in vivo may generate pathogenic variants with higher replication capacity, which will be a valuable resource as challenge virus in vaccine and cure studies.
Intronization enhances expression of S-protein and other transgenes challenged by cryptic splicing
Authors: Tomberg Kärt , Antunes Liliana , Pan YangYang , Hepkema Jacob , Garyfallos Dimitrios A. , Mahfouz Ahmed , Bradley Allan 
Published: September 2021

AbstractThe natural habitat of SARS-CoV-2 is the cytoplasm of a mammalian cell where it replicates its genome and expresses its proteins. While SARS-CoV-2 genes and hence its codons are presumably well optimized for mammalian protein translation, they have not been sequence optimized for nuclear expression. The cDNA of the Spike protein harbors over a hundred predicted splice sites and produces mostly aberrant mRNA transcripts when expressed in the nucleus. While different codon optimization strategies increase the proportion of full-length mRNA, they do not directly address the underlying splicing issue with commonly detected cryptic splicing events hindering the full expression potential. Similar splicing characteristics were also observed in other transgenes. By inserting multiple short introns throughout different transgenes, significant improvement in expression was achieved, including >7-fold increase for Spike transgene. Provision of a more natural genomic landscape offers a novel way to achieve multi-fold improvement in transgene expression.
Minos: variant adjudication and joint genotyping of cohorts of bacterial genomes
Authors: Hunt M. , Letcher B. , Malone K.M. , Nguyen G. , Hall M.B. , Colquhoun R.M. , Lima L. , Schatz M.C. , Ramakrishnan S. ,   CRyPTIC consortium, Iqbal Z. 
Published: September 2021

AbstractShort-read variant calling for bacterial genomics is a mature field, and there are many widely-used software tools. Different underlying approaches (eg pileup, local or global assembly, paired-read use, haplotype use) lend each tool different strengths, especially when considering non-SNP (single nucleotide polymorphism) variation or potentially distant reference genomes. It would therefore be valuable to be able to integrate the results from multiple variant callers, using a robust statistical approach to “adjudicate” at loci where there is disagreement between callers. To this end, we present a tool, Minos, for variant adjudication by mapping reads to a genome graph of variant calls. Minos allows users to combine output from multiple variant callers without loss of precision. Minos also addresses a second problem of joint genotyping SNPs and indels in bacterial cohorts, which can also be framed as an adjudication problem.We benchmark on 62 samples from 3 species (Mycobacterium tuberculosis, Staphylococcus aureus, Klebsiella pneumoniae) and an outbreak of 385 M. tuberculosis samples. Finally, we joint genotype a large M. tuberculosis cohort (N≈15k) for which the rifampicin phenotype is known. We build a map of non-synonymous variants in the RRDR (rifampicin resistance determining region) of the rpoB gene and extend current knowledge relating RRDR SNPs to heterogeneity in rifampicin resistance levels. We replicate this finding in a second M. tuberculosis cohort (N≈13k).Minos is released under the MIT license, available at https://github.com/iqbal-lab-org/minos.
Dry heat sterilization as a method to recycle N95 respirator masks: the importance of fit
Authors: Yuen John G. , Marshilok Amy C. , Benziger Peter Todd , Yan Shan , Cello Jeronimo , Stackhouse Chavis A. , Kisslinger Kim , Bock David C. , Takeuchi Esther S. , Takeuchi Kenneth J. , Wang Lei , Babu Sruthi , Itzkowitz Glen , Thanassi David , Knopf Daniel A. , Shroyer Kenneth R. 
Published: September 2021

AbstractIn times of crisis, including the current COVID-19 pandemic, the supply chain of filtering facepiece respirators, such as N95 respirators, are disrupted. To combat shortages of N95 respirators, many institutions were forced to decontaminate and reuse respirators. While several reports have evaluated the impact on filtration as a measurement of preservation of respirator function after decontamination, the equally important fact of maintaining proper fit to the users’ face has been understudied. In the current study, we demonstrate the complete inactivation of SARS-CoV-2 and preservation of fit test performance of N95 respirators following treatment with dry heat. We apply scanning electron microscopy with energy dispersive X-ray spectroscopy (SEM/EDS), X-ray diffraction (XRD) measurements, Raman spectroscopy, and contact angle measurements to analyze filter material changes as a consequence of different decontamination treatments. We further compared the integrity of the respirator after autoclaving versus dry heat treatment via quantitative fit testing and found that autoclaving, but not dry heat, causes the fit of the respirator onto the users face to fail, thereby rendering the decontaminated respirator unusable. Our findings highlight the importance to account for both efficacy of disinfection and mask fit when reprocessing respirators to for clinical redeployment.
A histidine cluster determines YY1-compartmentalized coactivators and chromatin elements in phase-separated super-enhancers
Authors: Wang Wenmeng , Qiao Shiyao , Li Guangyue , Yang Cuicui , Zhong Chen , Stovall Daniel B. , Shi Jinming , Li Dangdang , Sui Guangchao 
Published: September 2021

ABSTRACTAs an oncogenic transcription factor, Yin Yang 1 (YY1) regulates enhancer and promoter connection. However, gaps still exist in understanding how YY1 coordinates coactivators and chromatin elements to assemble super-enhancers. Here, we demonstrate that YY1 activates FOXM1 gene expression through forming liquid-liquid phase separation to compartmentalize both coactivators and enhancer elements. In the transactivation domain of YY1, a histidine cluster is essential for its activities of forming phase separation, which can be extended to additional proteins. Coactivators EP300, BRD4, MED1 and active RNA polymerase II are components of YY1-rich nuclear puncta. Consistently, histone markers for gene activation, but not repression, colocalize with YY1. Importantly, multiple enhancer elements and the FOXM1 promoter are bridged by YY1 to form super-enhancers. These studies propose that YY1 is a general transcriptional activator, and promotes phase separation with incorporation of major coactivators and stabilization by distal enhancers to activate target gene expression.
Non-canonical Wnt signaling promotes directed migration of intestinal stem cells to sites of injury
Authors: Hu Daniel Jun-Kit , Yun Jina , Elstrott Justin , Jasper Heinrich 
Published: September 2021

SummaryTissue regeneration after injury requires coordinated regulation of stem cell activation, division, and daughter cell differentiation, processes that are increasingly well understood in many regenerating tissues. How accurate stem cell positioning and localized integration of new cells into the damaged epithelium are achieved, however, remains unclear. Here we show that enteroendocrine cells coordinate stem cell migration towards a wound in the Drosophila intestinal epithelium. In response to injury, EEs release the N-terminal domain of the PTK7 orthologue, Otk, which activates non-canonical Wnt signaling in ISCs, promoting actin-based protrusion formation and ISC migration towards a wound. We find that this migratory behavior is closely linked to ISC proliferation, and that it is required for efficient tissue repair during injury. Our findings highlight the role of non-canonical Wnt signaling in regeneration of the intestinal epithelium, and identify EE-released ligands as critical coordinators of ISC migration.
Understanding aviation operators’ variability in advanced systems
Authors: Papanikou Maria , Kale Utku , Nagy András , Stamoulis Konstantinos 
Published: September 2021

Purpose
This study aims to identify variability in aviation operators in order to gain greater understanding of the changes in aviation professional groups. Research has commonly addressed human factors and automation in broad categories according to a group’s function (e.g., pilots, air traffic controllers [ATCOs], engineers). Accordingly, pilots and Air Traffic Controls (ATCOs) have been treated as homogeneous groups with a set of characteristics. Currently, critical themes of human performance in light of systems’ developments place the emphasis on quality training for improved situational awareness (SA), decision-making and cognitive load.

Design/methodology/approach
As key solutions centre on the increased understanding and preparedness of operators through quality training, the authors deploy an iterative mixed methodology to reveal generational changes of pilots and ATCOs. In total, 46 participants were included in the qualitative instrument and 70 in the quantitative one. Preceding their triangulation, the qualitative data were analysed using NVivo and the quantitative analysis was aided through descriptive statistics.

Findings
The results show that there is a generational gap between old and new generations of operators. Although positive views on advanced systems are being expressed, concerns about cognitive capabilities in the new systems, training and skills gaps, workload and role implications are presented.

Practical implications
The practical implications of this study extend to different profiles of operators that collaborate either directly or indirectly and that are critical to aviation safety. Specific implications are targeted on automation complacency, bias and managing information load, and training aspects where quality training can be aided by better understanding the occupational transitions under advanced systems.

Originality/value
In this paper, the authors aimed to understand the changing nature of the operators’ profession within the advanced technological context, and the perceptions and performance-shaping factors of pilots and ATCOs to define the generational changes.
The impact of bridging social capital in family firms' performance: exploring the mediation role of successor's social skills
Authors: Yezza Hedi , Chabaud Didier , Dana Léo Paul , Maalaoui Adnane 
Published: September 2021

PurposeThis paper investigates the impact of bridging social capital on the financial and non-financial performance of family businesses and explores the mediation role of social skills in the context of family succession.Design/methodology/approachA quantitative study, through questionnaires, was conducted among 105 Tunisian family firms that have experienced a family succession for at least one year. The PLS-SEM analysis method was used to test the research hypothesis.FindingsResults show that an increase in external social capital is positively associated with financial performance and family-centred non-economic goals, whereas social skills mediate this positive relationship.Originality/valueThe proposed model aims to test the direct effect of bridging social capital on family firms' performance and exploring the mediation role of the successor's social skills.
Resilient route selection of oversized cargo transport: the case of South Korea–Kazakhstan
Authors: Lu Wen , Choi Su-Beom , Yeo Gi-Tae 
Published: September 2021

PurposeResilient route selection for oversized cargoes, one of the general bulk cargoes, has not been adequately optimized in terms of using the Arctic route. This study solves the problem of selecting the optimal shipping routes for oversized cargoes from Busan (South Korea) to Balkhash (Kazakhstan).Design/methodology/approachThe study used the consistent fuzzy preference relation (CFPR) method, which is used to solve multi-criteria decision-making (MCDM) and uncertainty problems, to tackle the route selection. This method involves three procedures: first, the critical factors and alternative routes were obtained by the previous literature and an in-depth interview of experts of oversized cargo-handling with more than 20 years of working experience; second, the weightings for each critical factor were identified using the CFPR calculation process and third, alternative routes were evaluated using weighted critical factors.FindingsThe Northern Sea Route (NSR) combined with the inland waterways of Russia and Kazakhstan was first suggested for bulk carriers that handle oversized cargoes. The NSR could be a suitable route from Busan to Cape Kamenny of the Russian transshipment seaport, where oversized cargoes will be transferred to the river barge at Cape Kamenny, covering 4,913 km from the latter to Balkhash of Kazakhstan via the Ob/Irtysh River.Practical implicationsThis study equips stakeholders in route selection for cargoes with strategies and methods to improve transportation efficiently and enhance shipping routes between Asia and the Commonwealth of Independent States (CIS). In addition to oversized cargoes, coal and timber from Russia can be transported to Asia using inland waterways and the NSR, which can also be used to transport plant equipment for petroleum refineries among Asian countries.Originality/valueThis is the first study to evaluate the suitability of the Artic route for oversized cargoes from South Korea to Kazakhstan. It provides a comprehensive evaluation framework of multimodal shipping routes and offers references for decision-makers when dealing with similar problems.