bluuebunny/crossref_metadata_2025_split huggingface dataset:
p38δ genetic ablation protects female mice from anthracycline cardiotoxicity
Authors: George Sharon A , Kiss Alexi , Obaid Sofian N , Venegas Aileen , Talapatra Trisha , Wei Chapman , Efimova Tatiana , Efimov Igor R 
Published: March 2020

ABSTRACTBACKGROUNDThe efficacy of an anthracycline antibiotic doxorubicin (DOX) as a chemotherapeutic agent is limited by dose-dependent cardiotoxicity. DOX is associated with activation of intracellular stress signaling pathways including p38 MAPKs. While previous studies have implicated p38 MAPK signaling in DOX-induced cardiac injury, the roles of the individual p38 isoforms, specifically, of the alternative isoforms p38γ and p38δ, remain uncharacterized.OBJECTIVESTo determine the potential cardioprotective effects of p38γ and p38δ genetic deletion in mice subjected to acute DOX treatment.METHODSMale and female wild-type (WT), p38γ-/-, p38δ-/-and p38γ-/-δ-/-mice were injected with 30 mg/kg DOX and their survival was tracked for ten days. During this period cardiac function was assessed by echocardiography and electrocardiography and fibrosis by PicroSirius Red staining. Immunoblotting was performed to assess the expression of signaling proteins and markers linked to autophagy.RESULTSSignificantly improved survival was observed in p38δ-/-female mice post-DOX relative to WT females, but not in p38γ-/-or p38γ-/-δ-/-male or female mice. The improved survival in DOX-treated p38δ-/-females was associated with decreased fibrosis, increased cardiac output and LV diameter relative to DOX-treated WT females, and similar to saline-treated controls. Structural and echocardiographic parameters were either unchanged or worsened in all other groups. Increased autophagy, as evidenced by increased LC3-II level, and decreased mTOR activation was also observed in DOX-treated p38δ-/-females.CONCLUSIONSp38δ plays a crucial role in promoting DOX-induced cardiotoxicity in female mice by inhibiting autophagy. Therefore, p38δ targeting could be a potential cardioprotective strategy in anthracycline chemotherapy.NEW AND NOTEWORTHYThis study for the first time identifies the roles of the alternative p38γ and p38δ MAPK isoforms in promoting DOX-cardiotoxicity in a sex-specific manner. While p38γ systemic deletion did not affect DOX-cardiotoxicity, p38δ systemic deletion was cardioprotective in female but not in male mice. Cardiac structure and function were preserved in DOX-treated p38δ-/- females and autophagy was increased.
Identification of determinants of differential chromatin accessibility through a massively parallel genome-integrated reporter assay
Authors: Hammelman Jennifer , Krismer Konstantin , Banerjee Budhaditya , Gifford David K , Sherwood Richard 
Published: March 2020

AbstractA key mechanism in cellular regulation is the ability of the transcriptional machinery to physically access DNA. Pioneer transcription factors interact with DNA to open chromatin, which subsequently enables changes to gene expression during development, disease, or as a response to environmental stimuli. However, the regulation of DNA accessibility via the recruitment of transcription factors is difficult to understand in the context of the native genome because every genomic site is distinct in multiple ways. Here we introduce the Multiplexed Integrated Accessibility Assay (MIAA), a multiplexed parallel reporter assay which measures changes to genome accessibility as a result of the integration of synthetic oligonucleotide phrase libraries into a controlled, natively inaccessible genomic context. We apply MIAA to measure the effects of sequence motifs on cell type-specific DNA accessibility between mouse embryonic stem cells and embryonic stem cell-derived definitive endoderm cells, screening a total of 7,905 distinct phrases. MIAA is able to recapitulate differential accessibility patterns of 100-nt sequences derived from natively differential genomic regions, identifying the presence of E-box motifs common to epithelial-mesenchymal transition driver transcription factors in stem cell-specific accessible regions that become repressed during differentiation to endoderm. We further present causal evidence that a single binding motif for a key regulatory transcription factor is sufficient to open chromatin, and classify sets of stem cell-specific, endoderm-specific, and shared pioneer factor motifs. We also demonstrate that over-expression of two definitive endoderm transcription factors, Brachyury and FoxA2, results in changes to accessibility in phrases containing their respective DNA-binding motifs. Finally, we use MIAA results to explore the order of motif interactions and identify preferential motif ordering arrangements that appear to have an effect on accessibility.
Synonymous Dinucleotide Usage: A Codon-Aware Metric for Quantifying Dinucleotide Representation in Viruses
Authors: Lytras Spyros , Hughes Joseph 
Published: March 2020

AbstractDistinct patterns of dinucleotide representation, such as CpG and UpA suppression, are characteristic of certain viral genomes. Recent research has uncovered vertebrate immune mechanisms that select against specific dinucleotides in targeted viruses. This evidence highlights the importance of systematically examining the dinucleotide composition of viral genomes. We have developed a novel metric, called Synonymous Dinucleotide Usage (SDU), for quantifying dinucleotide representation in coding sequences. Our method compares the abundance of a given dinucleotide to the null hypothesis of equal synonymous codon usage in the sequence. We present a Python3 package,DinuQ, for calculating SDU and other relevant metrics. We have applied this method on two sets of invertebrate- and vertebrate-specific flaviviruses and rhabdoviruses. The SDU shows that the vertebrate viruses exhibit consistently greater under-representation of CpG dinucleotides in all three codon positions in both datasets. In comparison to existing metrics for dinucleotide quantification, the SDU allows for a statistical interpretation of its values by comparing it to a null expectation based on the codon table. Here we apply the method to viruses, but coding sequences of other living organisms can be analysed in the same way.
Architectural Mediator subunits are differentially essential for global transcription in yeast
Authors: Tourigny Jason P. , Schumacher Kenny , Devys Didier , Zentner Gabriel E. 
Published: March 2020

SummaryThe modular Mediator complex is a coactivator of RNA polymerase II transcription. We show that depletion of the main complex scaffold Med14 or the head module scaffold Med17 is lethal and results in global transcriptional downregulation in yeast, though Med17 removal has a markedly greater negative effect. Depletion of Med14 or Med17 impairs pre-initiation complex (PIC) assembly similarly, suggesting that the differential transcriptional effects observed are not due to differing extents of defective PIC formation. Co-depletion of Med14 and Med17 reduced transcription and TFIIB promoter occupancy similarly to Med17 ablation alone, suggesting that the independent head module can weakly stimulate transcriptionin vivo, though not to a level that maintains viability. We suggest that, while the structural integrity of complete Mediator and the head module are both important for PIC assembly, the head module additionally promotes optimal PIC function and is thus the key functional module of Mediator in this regard.
Designing and Comparing Optimised Pseudo-Continuous Arterial Spin Labelling Protocols for Measurement of Cerebral Blood Flow
Authors: Woods Joseph G. , Chappell Michael A. , Okell Thomas W. 
Published: March 2020

1.AbstractArterial Spin Labelling (ASL) is a non-invasive, non-contrast, perfusion imaging technique which is inherently SNR limited. It is, therefore, important to carefully design scan protocols to ensure accurate measurements. Many pseudo-continuous ASL (PCASL) protocol designs have been proposed for measuring cerebral blood flow (CBF), but it has not yet been demonstrated which design offers the most accurate and repeatable CBF measurements. In this work, a wide range of literature PCASL protocols, including single-delay, sequential and time-encoded multi-timepoint protocols, and several novel protocol designs, which are hybrids of time-encoded and sequential multi-timepoint protocols, were first optimised using a Cramér-Rao Lower Bound framework and then compared for CBF accuracy and repeatability using Monte Carlo simulations and in vivo experiments. It was found that several multi-timepoint protocols produced more confident, accurate, and repeatable CBF estimates than the single-delay protocol, while also generating maps of arterial transit time. One of the novel hybrid protocols, HybridT1-adj, was found to produce the most confident, accurate and repeatable CBF estimates of all protocols tested in both simulations and in vivo (24%, 47%, and 28% more confident, accurate, and repeatable than single-PLD in vivo). The HybridT1-adjprotocol makes use of the best aspects of both time-encoded and sequential multi-timepoint protocols and should be a useful tool for accurately and efficiently measuring CBF.
The INO80 ATP-dependent chromatin remodelling complex alleviates stalled Polymerase II to promote non-coding RNA transcription termination
Authors: Luzzi Sara , Szachnowski Ugo , Greener Sarah , Schumacher Kenny , Fulton Stuart , Walton Chloe , Gautier Camille , Han Kang Hoo , Darke Jack , Piccinno Rossana , Lafon Anne , Pugh B. Franklin , Devys Didier , Tora Laszlo , Morillon Antonin , Papamichos-Chronakis Manolis 
Published: March 2020

ABSTRACTCo-transcriptional RNA quality control is essential for gene expression. However, its regulation remains poorly understood. Here, we report that the evolutionarily conserved ATP-dependent chromatin remodelling INO80 complex promotes transcription termination by the non-coding RNA quality control pathway inS. cerevisiae. Loss of INO80 leads to accumulation of stalled RNA Polymerase II preferentially at promoter-proximal pausing sites, compromising Pol II processivity and hindering transcription elongation. We reveal that binding of RNA surveillance and non-coding transcription termination factors to promoter-proximal mRNA regions is associated with increased promoter-proximal pausing. INO80 counteracts promoter-proximal stalling of genes attenuated by the Nrd1-Nab3-Sen1 (NNS) non-coding transcription termination complex, promoting their expression. We show that INO80 interacts with Nrd1 and the Nab2 RNA surveillance factorin vivo. Absence of INO80 leads to defective transcription termination by the Nrd1-Nab3-Sen1 (NNS) complex. We demonstrate that INO80 facilitates the recruitment of Nab2 at non-coding transcription termination sites and its association with promoter-proximally terminated mRNA transcripts. Finally, we provide evidence that INO80 promotes the release of stalled RNA Polymerase II from a non-coding transcription termination site. Collectively, our work suggests that the INO80 complex regulates transcription by removal of stalled Polymerase, implicating a chromatin-based mechanism for non-coding and premature transcription termination in gene expression.
A Microfluidic Platform for Functional Testing of Cancer Drugs on Intact Tumor Slices
Authors: Rodriguez A.D , Horowitz L.F , Castro K. , Kenerson H. , Bhattacharjee N. , Gandhe G. , Raman A. , Monnat R. J. , Yeung R. , Rostomily R.C. , Folch A. 
Published: March 2020

AbstractPresent approaches to assess cancer treatments are often inaccurate, costly, and/or cumbersome. Functional testing platforms that use live tumor cells are a promising tool both for drug development and for identifying the optimal therapy for a given patient, i.e. precision oncology. However, current methods that utilize patient-derived cells from dissociated tissue typically lack the microenvironment of the tumor tissue and/or cannot inform on a timescale rapid enough to guide decisions for patient-specific therapy. We have developed a microfluidic platform that allows for multiplexed drug testing of intact tumor slices cultured on a porous membrane. The device is digitally-manufactured in a biocompatible thermoplastic by laser-cutting and solvent bonding. Here we describe the fabrication process in detail, we characterize the fluidic performance of the device, and demonstrate on-device drug-response testing with tumor slices from xenografts and from a patient colorectal tumor.
Limited Environmental Serine Confers Sensitivity to PHGDH Inhibition in Brain Metastasis
Authors: Ngo Bryan , Kim Eugenie , Osorio-Vasquez Victoria , Doll Sophia , Bustraan Sophia , Luengo Alba , Davidson Shawn M. , Ali Ahmed , Ferraro Gino D. , Kang Diane , Ni Jing , Liang Roger , Plasger Ariana , Kastenhuber Edward R. , Eskandari Roozbeh , Bacha Sarah , Siriam Roshan K. , Bakhoum Samuel F. , Mullarky Edouard , Snuderl Matija , Cotzia Paolo , Mainolfi Nello , Suri Vipin , Friedman Adam , Manfredi Mark , Sabatini David M. , Jones Drew , Yu Min , Zhao Jean J. , Jain Rakesh K. , Vander Heiden Matthew G. , Hernando Eva , Mann Matthias , Cantley Lewis C. , Pacold Michael E. 
Published: March 2020

AbstractA hallmark of metastasis is the adaptation of tumor cells to new environments. Although it is well established that the metabolic milieu of the brain is severely deprived of nutrients, particularly the amino acids serine and its catabolite glycine, how brain metastases rewire their metabolism to survive in the nutrient-limited environment of the brain is poorly understood. Here we demonstrate that cell-intrinsicde novoserine synthesis is a major determinant of brain metastasis. Whole proteome comparison of triple-negative breast cancer (TNBC) cells that differ in their capacity to colonize the brain reveals that 3-phosphoglycerate dehydrogenase (PHGDH), which catalyzes the rate-limiting step of glucose-derived serine synthesis, is the most significantly upregulated protein in cells that efficiently metastasize to the brain. Genetic silencing or pharmacological inhibition of PHGDH attenuated brain metastasis and improved overall survival in mice, whereas expression of catalytically active PHGDH in a non-brain trophic cell line promoted brain metastasis. Collectively, these findings indicate that nutrient availability determines serine synthesis pathway dependence in brain metastasis, and suggest that PHGDH inhibitors may be useful in the treatment of patients with cancers that have spread to the brain.Statement of SignificanceOur study highlights how limited serine and glycine availability within the brain microenvironment potentiates tumor cell sensitivity to serine synthesis inhibition. This finding underscores the importance of studying cancer metabolism in physiologically-relevant contexts, and provides a rationale for using PHGDH inhibitors to treat brain metastasis.
Analysis of reliability and its characteristics of a k-out-of-n network incorporating copula
Authors: Nautiyal Nisha , Singh S.B. , Bisht Soni 
Published: March 2020

PurposeThe present paper focuses on the evaluation of reliability and its characteristics (Mean time to failure and Sensitivity) of a k-out-of-n network.Design/methodology/approachThe minimal cuts of the network have been evaluated for different nodes in this paper, using an algorithm. With the help of these cuts, reliability and its characteristics are obtained using Gumbel–Hougaard family of the copula.FindingsThe present paper proposes to compute the reliability and its measures of the k-out-of-n network using the minimal cuts and copula methodology. The completely failed nodes of the network have been repaired using Gumbel–Hougaard family of the copula.Originality/valueIn this paper, the reliability of a k-out-of-n network has been evaluated by first calculating k-out-of-n minimal cuts, and the failed nodes have also been repaired using Gumbel–Hougaard family of the copula, unlike as done in the past.
To lead or not to lead: that is the (courageous) question
Authors: Bajer Javier 
Published: March 2020

Purpose
The purpose of this paper is to challenge the constructs regularly used by organisations around the world for the development of leadership.

Design/methodology/approach
This is an opinion piece based on direct observation of hundreds of organisations over the years.

Findings
The regular approaches used for the development of leadership skills in organisations have consistently failed to deliver against its promise. Moreover, it is often the case that organisations pursue new “solutions” to bridge the leadership gap, often to discover that their new approach not only failed to develop the skills needed but also had the side effect of distracting vast amounts of attention. This paper describes what, if not the various taxonomies that describe, “good leadership” looks like really and how it delivers sustainable and effective leadership transformation.

Originality/value
This piece challenges the status quo, offering a more powerful way of connecting people with the purpose of their work, increasing the impact that individual leadership could have in the creation of value for all stakeholders, including themselves.
Attitudes toward organic products: a cross-national comparison and scale validation
Authors: Sarabia-Andreu Francisco , Sarabia-Sanchez Francisco J. , Parra-Meroño María Concepción , Moreno-Albaladejo Pablo 
Published: March 2020

Purpose
This study aims to examine the formal and metric properties of Gil et al.’s (2000) scale of attitudes toward organic products, which is the most popular scale to measure these attitudes.

Design/methodology/approach
The sample consisted of 4,992 household shoppers living in Hong Kong, Germany, Norway, Spain and the UK. The questionnaire was distributed using a third-party consumer panel, and the fieldwork was conducted using computer-assisted Web interviewing. The approach was based on confirmatory factor analysis and measurement of invariance, as well as format analysis using a wording-syntactic and semantic descriptive method.

Findings
The scale reflects an attitude-toward-object model approach. Its use has been heavily varied (in terms of wording, item semantics and the attributes to be measured). A two-factor structure that meets the metric conditions (reliability and validity) is found. However, the analysis of invariance shows that the scale behaves differently in different countries.

Research limitations/implications
This scale offers a good starting point for measuring attitudes toward organic products. However, it requires refinement to adapt to consumer evolution and improve its metric validity. Verification of its applicability in cross-national studies is recommended.

Originality/value
To the best of the authors’ knowledge, this is the first study that assesses the format and quantitative characteristics of this scale on a cross-national level. For scholars and companies with international interests, preventing the use of scales with poor properties at the transnational level can improve the design of future studies and save money through a more informed choice of attitudinal scale.
Safety evaluation of four entomopathogenic nematode species against two silkworm species
Authors: Dong Hui , Bi Yu , Wang Jia‐Lin , Liu Yan‐Qun , Wang Huan 
Published: March 2020

AbstractChinese oak silkworm (Antheraea pernyi) and mulberry silkworm (Bombyx mori) are economically important insects used for silk production and food resource. Entomopathogenic nematodes (EPNs) from the families of Steinernematidae and Heterorhabditidae are beneficial organisms currently considered in biological control. In this paper, we evaluated survival of two silkworm species exposed to fourSteinernemaspecies which are widely applied in pest control. The results showed that among fourSteinernemaspecies,S. bicornutumandS. feltiaedid not have an effect on the larval survival to the two silkworm species, whereasS. carpocapsaeandS. glaseridid have an effect. EachSteinernemaspecies poses no threat to hatchability of eggs, pupation rate, larval durations and cocoon shell ratio.
Colorectal peritoneal metastases: pathogenesis, diagnosis and treatment options – an evidence‐based update
Authors: Narasimhan Vignesh , Ooi Geraldine , Michael Michael , Ramsay Robert , Lynch Craig , Heriot Alexander 
Published: March 2020

AbstractPeritoneal metastases confer the worst survival among all sites in patients with metastatic colorectal cancer. They develop largely through transcoelomic spread, with a sequence of events that allow cells to first detach from primary tumours, survive in the peritoneal environment, attach to the peritoneal surface of organs and migrate into the submesothelial space to create a microenvironment conducive to metastatic growth. Diagnostic challenges have previously hindered early identification of peritoneal metastases. While advances in diagnostic modalities have improved our ability to identify peritoneal metastases, lesions under 0.5 cm remain challenging to detect. The advent of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC) can offer selected patients with colorectal peritoneal metastases a favourable long‐term survival. Recent trials, however, have cast doubts on the efficacy of HIPEC, with the recent PRODIGE 7 trial showing no benefit from oxaliplatin based HIPEC in addition to good quality cytoreductive surgery in resectable disease. While peritoneal recurrence can be reliably predicted from high‐risk features in primary tumours such as a perforated cancer, ovarian metastases or T4a cancers, the use of prophylactic second look surgery with HIPEC or adjuvant HIPEC failed to demonstrate any survival benefit in high‐risk cases in recent clinical trials, raising further questions about the efficacy of HIPEC. With high failure rates from systemic chemotherapy in unresectable disease, novel surgical techniques such as pressurized intraperitoneal aerolized chemotherapy are being investigated in clinical trials worldwide. Further collaborative research is needed to explore newer avenues of treatment for this poor prognostic cohort.
The effects of acute and sustained cannabidiol dosing for seven days on the haemodynamics in healthy men: A randomised controlled trial
Authors: Sultan Salahaden R. , O'Sullivan Saoirse E. , England Timothy J. 
Published: March 2020

BackgroundIn vivo studies show that cannabidiol (CBD) acutely reduces blood pressure (BP) in men. The aim of this study was to assess the effects of repeated CBD dosing on haemodynamics.MethodsTwenty‐six healthy males were given CBD (600 mg) or placebo orally for seven days in a randomised, placebo‐controlled, double‐blind, parallel study (n = 13/group). Cardiovascular parameters were assessed at rest and in response to isometric exercise after acute and repeated dosing using Finometer®, Vicorder® and Duplex ultrasound.ResultsCompared to placebo, CBD significantly reduced resting mean arterial pressure (P = .04, two‐way ANOVA, mean difference (MD) –2 mmHg, 95% CI ‐3.6 to −0.3) after acute dosing, but not after repeated dosing. In response to stress, volunteers who had taken CBD had lower systolic BP after acute (P = .001, two‐way ANOVA, MD −6 mmHg, 95% CI –10 to −1) and repeated (P = .02, two‐way ANOVA, MD −5.7 mmHg, 95% CI –10 to −1) dosing. Seven days of CBD increased internal carotid artery diameter (MD +0.55 mm, P = .01). Within the CBD group, repeated dosing reduced arterial stiffness by day 7 (pulse wave velocity; MD −0.44 m/s, P = .05) and improved endothelial function (flow mediation dilatation, MD +3.5%, P = .02, n = 6 per group), compared to day 1.ConclusionCBD reduces BP at rest after a single dose but the effect is lost after seven days of treatment (tolerance); however, BP reduction during stress persists. The reduction in arterial stiffness and improvements in endothelial function after repeated CBD dosing are findings that warrant further investigation in populations with vascular diseases.