bluuebunny/crossref_metadata_2025_split huggingface dataset:
Time dependent response of daunorubicin on cytotoxicity, cell cycle and DNA repair in acute lymphoblastic leukaemia
Authors: Al-Aamri Hussain Mubarak , Ku Heng , Irving Helen R , Tucci Joseph , Meehan-Andrews Terri , Bradley Christopher 
Published: June 2018

AbstractDaunorubicin is commonly used in the treatment of acute lymphoblastic leukaemia (ALL). Various mechanisms of action for daunorubicin have been proposed and its action is likely to be multi-modal. The aim of this study was to explore the kinetics of double strand break (DSB) formation of three ALL cell lines following exposure to daunorubicin and to investigate the effects of daunorubicin on the cell cycle and the protein kinases involved in specific checkpoints following DNA damage and recovery periods. Three ALL cell lines CCRF-CEM and MOLT-4 derived from T lymphocytes and SUP-B15 derived from B lymphocytes were examined following 4 hours treatment with daunorubicin chemotherapy and varying recovery periods. Daunorubicin induced different degrees of toxicity in all cell lines and consistently generated reactive oxygen species. Daunorubicin was more potent at inducing DSB in MOLT-4 and CCRF-CEM cell lines while SUP-B15 cells showed delays in DSB repair and significantly more resistance to daunorubicin compared to the other cell lines as measured by γH2AX assay. Daunorubicin also causes cell cycle arrest in all three cell lines at different checkpoints at different times. These effects were not due to mutations in Ataxia–telangiectasia mutated (ATM) as sequencing revealed none in any of the three cell lines. However, p53 was phosphorylated at serine 15 only in CCRF-CEM and MOLT-4 but not in SUP-B15 cells. The lack of active p53 may be correlated to the increase of SOD2 in SUP-B15 cells. The delay in DSB repair and lower sensitivity to daunorubicin seen in the B lymphocyte derived SUP-B15 cells could be due to loss of function of p53 thus causing variations in the DNA repair pathways.
Outcomes of early NIH-funded investigators: Experience of the National Institute of Allergy and Infectious Diseases
Authors: Haggerty Patricia A. , Fenton Matthew J. 
Published: June 2018

AbstractSurvival of junior scientists in academic biomedical research is difficult in today’s highly competitive funding climate. National Institute of Health (NIH) data on first-time R01 grantees indicate the rate at which early investigators drop out from a NIH-supported research career is most rapid 4 to 5 years from the first R01 award. The factors associated with a high risk of dropping out, and whether these factors impact all junior investigators equally, are unclear. We identified a cohort of 1,496 investigators who received their first R01-equivalent (R01-e) awards from the National Institute of Allergy and Infectious Diseases between 2003 and 2010, and studied all their subsequent NIH grant applications through 2016. Ultimately, 57% of the cohort were successful in obtaining new R01-e funding, despite highly competitive conditions. Among those investigators who failed to compete successfully for new funding (43%), the average time to dropping out was 5 years. Investigators who successfully obtained new grants showed remarkable within-person consistency across multiple grant submission behaviors, including submitting more applications per year, more renewal applications, and more applications to multiple NIH Institutes. Funded investigators appeared to have two advantages over their unfunded peers at the outset: they had better scores on their first R01-e grants and they demonstrated an early ability to write applications that would be scored, not triaged. The cohort rapidly segregated into two very different groups on the basis of PI consistency in the quality and frequency of applications submitted after their first R01-e award. Lastly, we identified a number of specific demographic factors, intitutional characteristics, and grant submission behaviors that were associated with successful outcomes, and assessed their predictive value and relative importance for the likelihood of obtaining additional NIH funding.
A comparative analysis of label-free liquid chromatography-mass spectrometry liver proteomic profiles highlights metabolic differences between pig breeds
Authors: Bovo Samuele , Luca Alessio Di , Galimberti Giuliano , Dall’Olio Stefania , Fontanesi Luca 
Published: June 2018

AbstractLiver is a complex organ governing several physiological processes that define biological mechanisms affecting growth, feed efficiency and performance traits in all livestock species, including the pig. Proteomics may contribute to better understand the relationship between liver functions and complex production traits in pigs and to characterize this specie as biomedical model. This study applied, for the first time, a label-free liquid chromatography-mass spectrometry (LC-MS) proteomic approach to compare the liver proteome profiles of two important heavy pig breeds, Italian Duroc (IDU) and Italian Large White (ILW). Liver specimens were collected (after slaughtering) from performance tested pigs of these two breeds, raised in standard conditions. The label-free LC-MS method captured a total of 501 proteins of which 200 were subsequently considered in the between breeds comparison. A statistical pipeline based on the sparse Partial Least Squares Discriminant Analysis (sPLS-DA), coupled with stability and significance tests, was applied for the identification of up or down regulated proteins between breeds. Analyses revealed a total of 25 proteins clearly separating IDU and ILW pigs. Among the top proteins differentiating the two breeds ACAA2 and CES3 were up-regulated in ILW and HIST2H2BF and KHK were up-regulated in IDU. FASN, involved in fatty acid metabolism and encoded by a gene located in a QTL region for fatty acid composition, was up-regulated in ILW. Protein interaction analysis showed that 16 of these proteins were connected in one big module. Functional analyses indicated that differentially expressed proteins were involved in several biological processes related to the metabolism of lipids, amino-acids, carbohydrates, cofactors and antibiotics/drugs, supporting that these functions might distinguish IDU and ILW pigs. This comparative proteomic analysis of the porcine liver highlighted several biological factors that could determine the peculiar production potentials of these two heavy pig breeds, derived by their different genetic backgrounds.
A framework for translation of genomic responses from mouse models to human inflammatory disease contexts
Authors: Brubaker Douglas K. , Proctor Elizabeth A. , Haigis Kevin M. , Lauffenburger Douglas A. 
Published: June 2018

ABSTRACTThe high failure rate of therapeutics showing promise in mouse disease models to translate to patients is a pressing challenge in biomedical science. However, mouse models are a useful tool for evaluating mechanisms of disease and prioritizing novel therapeutic agents for clinical trials. Though retrospective studies have examined the fidelity of mouse models of inflammatory disease to their respective human in vivo conditions, approaches for prospective translation of insights from mouse models to patients remain relatively unexplored. Here, we develop a semi-supervised learning approach for prospective inference of disease-associated human in vivo differentially expressed genes and pathways from mouse model experiments. We examined 36 transcriptomic case studies where comparable phenotypes were available for mouse and human inflammatory diseases and assessed multiple computational approaches for inferring human in vivo biology from mouse model datasets. We found that a semi-supervised artificial neural network identified significantly more true human in vivo associations than interpreting mouse experiments directly (95% CI on F-score for mouse experiments [0.090, 0.175], neural network [0.278, 0.375], p = 0.00013). Our study shows that when prospectively evaluating biological associations in mouse studies, semi-supervised learning approaches combining mouse and human data for biological inference provides the most accurate assessment of human in vivo disease and therapeutic mechanisms. The task of translating insights from model systems to human disease contexts may therefore be better accomplished by the use of systems modeling driven approaches.Author SummaryComparison of genomic responses in mouse models and human disease contexts is not sufficient for addressing the challenge of prospective translation from mouse models to human disease contexts. Here, we address this challenge by developing a semi-supervised machine learning approach that combines supervised modeling of mouse experiment datasets with unsupervised modeling of human disease-context datasets to predict human in vivo differentially expressed genes and pathways as if the model system experiment had been run in the human cohort. A semi-supervised version of a feed forward artificial neural network was the most efficacious model for translating experimentally derived mouse molecule-phenotype associations to the human in vivo disease context. We find that computational generalization of signaling insights from mouse to human contexts substantially improves upon direct generalization of mouse experimental insights and argue that such approaches can facilitate more clinically impactful translation of insights from preclinical studies in model systems to patients.
Reconstruction of post-synaptic potentials by reverse modeling of local field potentials
Authors: Yochum Maxime , Modolo Julien , Benquet Pascal , Wendling Fabrice 
Published: June 2018

AbstractAmong electrophysiological signals, Local Field Potentials (LFPs) are extensively used to study brain activity, either in vivo or in vitro. LFPs are recorded with extracellular electrodes implanted in brain tissue. They reflect intermingled excitatory and inhibitory processes in neuronal assemblies. In cortical structures, LFPs mainly originate from the summation of post-synaptic potentials (PSPs), either excitatory (ePSPs) and inhibitory (iPSPs) generated at the level of pyramidal cells. The challenging issue, addressed in this paper, is to estimate, from a single extracellularly-recorded signal, both ePSP and iPSP components of the LFP. The proposed method is based on a model-based reverse engineering approach in which the measured LFP is fed into a physiologically-grounded neural mass model (mesoscopic level) in order to estimate the synaptic activity of a sub-population of pyramidal cells interacting with local GABAergic interneurons. The method was first validated using simulated LFPs for which excitatory and inhibitory components are known a priori and can thus serve as a ground truth. It was then evaluated on in vivo data (PTZ-induced seizures, rat; PTZ-induced excitability increase, mouse; epileptiform discharges, mouse) and on in clinico data (human seizures recorded with depth-EEG electrodes). Under these various conditions, results showed that the proposed reverse engineering method provides a reliable estimation of the average excitatory and inhibitory post-synaptic potentials at the origin of the measured LFPs. They also indicated that the method allows for monitoring of the excitation/inhibition ratio. The method has potential for multiple applications in neuroscience, typically when a time tracking of local excitability changes is required.
Lysophosphatidic acid produced by Autotaxin acts as an allosteric modulator of its catalytic efficiency
Authors: Salgado-Polo Fernando , Fish Alex , Matsoukas Minos-Timotheos , Heidebrecht Tatjana , Keune Willem-Jan , Perrakis Anastassis 
Published: June 2018

AbstractAutotaxin is a secreted phosphodiesterase that converts lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA). LPA controls key cellular responses such as migration, proliferation and survival, implicating ATX-LPA signalling in various (patho)physiological processes and establishing it as a drug target. ATX structural and functional studies have revealed an orthosteric and an allosteric site, the “pocket” and the “tunnel”. Here, we revisit the kinetics of the ATX catalytic cycle in light of allosteric regulation, dissecting the different steps and pathways that lead to LPC hydrolysis. Consolidating all experimental kinetics data to a comprehensive catalytic model supported by molecular modelling simulations, suggests a positive feedback mechanism, regulated by the abundance of the LPA products activating hydrolysis of different LPC species. Our results complement and extend current understanding of ATX hydrolysis in light of the allosteric regulation by produced LPA species, and have implications for the design and application of orthosteric and allosteric ATX inhibitors.
ERK1/2-dependent activation of FCHSD2 drives cancer cell-selective regulation of clathrin-mediated endocytosis
Authors: Xiao Guan-Yu , Mohanakrishnan Aparna , Schmid Sandra L. 
Published: June 2018

AbstractClathrin-mediated endocytosis (CME) regulates the uptake of cell surface receptors, as well as their downstream signaling activities. We recently reported that signaling reciprocally regulates CME in cancer cells and that the crosstalk can contribute to cancer progression. To further explore the nature and extent of the crosstalk between signaling and CME in cancer cell biology, we analyzed a panel of oncogenic signaling kinase inhibitors for their effects on CME. Inhibition of several kinases selectively affected CME function in cancer cells. Among these, ERK1/2 inhibition selectively inhibited CME in cancer cells by decreasing the rate of CCP initiation. We identified an ERK1/2 substrate, the FCH/F-BAR and SH3 domain-containing protein, FCHSD2, as being essential for the ERK1/2-dependent effects on CME and CCP initiation. ERK1/2 phosphorylation activates FCHSD2 and regulates EGFR endocytic trafficking as well as downstream signaling activities. Loss of FCHSD2 activity in non-small-cell lung cancer cells leads to increased cell surface expression and altered signaling downstream of EGFR, resulting in enhanced cell proliferation and migration. The expression level of FCHSD2 is positively correlated with higher cancer patient survival rate, suggesting that FCHSD2 negatively affects cancer progression. These findings provide new insight into the mechanisms and consequences of the reciprocal regulation of signaling and CME in cancer cells.SignificanceClathrin-mediated endocytosis (CME) determines the internalization of receptors and their downstream signaling. We discovered that CME is differentially regulated by specific signaling kinases in cancer cells. In particular, ERK1/2-mediated phosphorylation of the FCH/F-BAR and double SH3 domains-containing protein 2 (FCHSD2) regulates CME, and the trafficking and signaling activities of EGF receptors. This reciprocal interaction negatively regulates cancer proliferation and migration. The expression level of FCHSD2 is positively correlated with higher cancer patient survival rates. This study identifies signaling pathways that impinge on the endocytic machinery and reveals a molecular nexus for crosstalk between intracellular signaling and CME. Cancer cells specifically adapt this crosstalk as a determinant for tumor progression, which has implications for novel therapeutics against cancers.
Effects of Human Sex Chromosome Dosage on Spatial Chromosome Organization
Authors: Jowhar Ziad , Shachar Sigal , Gudla Prabhakar R. , Wangsa Darawalee , Torres Erin , Russ Jill L. , Pegoraro Gianluca , Ried Thomas , Raznahan Armin , Misteli Tom 
Published: June 2018

AbstractSex chromosome aneuploidies (SCAs) are common genetic syndromes characterized by the presence of an aberrant number of X and Y chromosomes due to meiotic defects. These conditions impact structure and function of diverse tissues, but the proximal effects of SCA on genome organization are unknown. Here, to determine the consequences of SCAs on global genome organization, we have analyzed multiple architectural features of chromosome organization in a comprehensive set of primary cells from SCA patients with various ratios of X and Y chromosomes by use of imaging-based high-throughput Chromosome Territory Mapping (HiCTMap). We find that X chromosome supernumeracy does not affect the size, volume or nuclear position of the Y chromosome or an autosomal chromosome. In contrast, the active X chromosome undergoes architectural changes as a function of increasing X copy number, as measured by a decrease in size and an increase in circularity, which is indicative of chromatin compaction. With Y chromosome supernumeracy, Y chromosome size is reduced suggesting higher chromatin condensation. The radial positioning of chromosomes is unaffected in SCA karyotypes. Taken together, these observations document changes in genome architecture in response to alterations in sex chromosome numbers and point to trans-effects of dosage compensation on chromosome organization.
Elucidation of the Mechanisms of Long-Distance mRNA Movement in aNicotiana benthamiana/Tomato Heterograft System
Authors: Xia Chao , Zheng Yi , Huang Jing , Zhou Xiangjun , Li Rui , Zha Manrong , Wang Shujuan , Huang Zhiqiang , Lan Hai , Turgeon Robert , Fei Zhangjun , Zhang Cankui 
Published: June 2018

AbstractRecent heterograft analyses showed that large-scale messenger RNA (mRNA) movement takes place in the phloem, but the number of mobile transcripts reported varies widely. However, our knowledge of the mechanisms underlying large-scale mRNA movement remains limited. In this study, using a Nicotiana benthamiana/tomato (Solanum lycopersicum) heterograft system and a transgenic approach involving potato (Solanum tuberosum), we found that: (1) the overall mRNA abundance in the leaf is not a good indicator of transcript mobility to the root; (2) increasing the expression levels of nonmobile mRNAs in the companion cells does not promote their mobility; (3) mobile mRNAs undergo degradation during their movement; and (4) some mRNAs arriving in roots move back to shoots. These results indicate that mRNA movement has both regulated and unregulated components. The cellular origins of mobile mRNAs may differ between herbaceous and woody species. Taken together, these findings suggest that the long-distance movement of mRNAs is a complex process and that elucidating the physiological roles associated with this movement is challenging but remains an important task for future research.
It is not always bad news
Authors: McNally Mary-Anne , Maroun Warren 
Published: June 2018

Purpose
The purpose of this paper is to challenge the notion that non-financial reporting is mainly about impression management or is only a superficial response to the hegemonic challenges posed by the sustainability movement. It focuses on the most recent development in sustainability reporting (integrated reporting) as an example of how accounting for financial and non-financial information has the potential to expand the scope of accounting systems, promote meaningful changes to reporting processes and provide a broader perspective on value creation.

Design/methodology/approach
The research focuses on an African eco-tourism company which has its head office in South Africa. A case study method is used to highlight differences in the presentation of an integrated business model according to the case entity’s integrated reports and how individual preparers interpret the requirement to prepare those reports. Data are collected using detailed interviews with all staff members involved in the preparation process. These are complemented by a review of the minutes of the company’s sustainability workshops and integrated reports.

Findings
A decision by the case organisation to prepare an integrated report gives rise to different forms of resistance which limits the change potential of the integrated reporting initiative. Resistance does not, however, preclude reform. Even when individual preparers are critical of the changes to the corporate reporting environment, accounting for financial and non-financial information expands the scope of the conventional accounting system which facilitates broader management control and promotes a more integrated conception of “value”.

Research limitations/implications
Integrated reporting should not be dismissed as only an exercise in corporate reporting and disclosure; it has a transformative potential which, given time, can enable new ways of managing business processes and articulating value creation.

Originality/value
This study answers the calls for primary evidence on how the requirement or recommendation to prepare an integrated report is being interpreted and applied by individual preparers. The findings add to the limited body of interpretive research on the change potential of new reporting frameworks. In doing so, the research provides theoretical support for developing arguments which challenge the conventional position that integrated reporting is little more than an exercise in impression management.
“Integrated reporting is like God: no one has met Him, but everybody talks about Him”
Authors: Gibassier Delphine , Rodrigue Michelle , Arjaliès Diane-Laure 
Published: June 2018

PurposeThe purpose of this paper is to analyze the process through which an International Integrated Reporting Council (IIRC) pilot company adopted “integrated reporting” (IR), a management innovation that merges financial and non-financial reporting.Design/methodology/approachA seven-year longitudinal ethnographic study based on semi-structured interviews, observations, and documentary evidence is used to analyze this multinational company’s IR adoption process from its decision to become an IIRC pilot organization to the publication of its first integrated report.FindingsFindings demonstrate that the company envisioned IR as a “rational myth” (Hatchuel, 1998; Hatchuel and Weil, 1992). This conceptualization acted as a springboard for IR adoption, with the mythical dimension residing in the promise that IR had the potential to portray global performance in light of the company’s own foundational myth. The company challenged the vision of IR suggested by the IIRC to stay true to its conceptualization of IR and eventually chose to implement its own version of an integrated report.Originality/valueThe study enriches previous research on IR and management innovations by showing how important it is for organizations to acknowledge the mythical dimension of the management innovations they pursue to support their adoption processes. These findings, suggest that myths can play a productive role in transforming business (reporting) practices. Some transition conditions that make this transformation possible are identified and the implications of these results for the future of IR, sustainability, and accounting more broadly are discussed.