bluuebunny/crossref_metadata_2025_split huggingface dataset:
Co-expression analysis reveals interpretable gene modules controlled bytrans-acting genetic variants
Authors: Kolberg Liis , Kerimov Nurlan , Peterson Hedi , Alasoo Kaur 
Published: April 2020

AbstractBackgroundDeveloping novel therapies for complex disease requires better understanding of the causal processes that contribute to disease onset and progression. Althoughtrans-acting gene expression quantitative trait loci (trans-eQTLs) can be a powerful approach to directly reveal cellular processes modulated by disease variants, detectingtrans-eQTLs remains challenging due to their small effect sizes and large number of genes tested. However, if a singletrans-eQTL controls a group of co-regulated genes, then multiple testing burden can be greatly reduced by summarising gene expression at the level of co-expression modules prior totrans-eQTL analysis.ResultsWe analysed gene expression and genotype data from six blood cell types from 226 to 710 individuals. We inferred gene co-expression modules with five methods on the full dataset, as well as in each cell type separately. We detected a number of established co-expression moduletrans-eQTLs, such as the monocyte-specific associations at theIFNB1andLYZloci, as well as a platelet-specificARHGEF3locus associated with mean platelet volume. We also discovered a noveltransassociation near theSLC39A8gene in LPS-stimulated monocytes. Here, we linked an early-responsecis-eQTL of theSLC39A8gene to a module of co-expressed metallothionein genes upregulated more than 20 hours later and used motif analysis to identify zinc-induced activation of the MTF1 transcription factor as a likely mediator of this effect.ConclusionsOur analysis provides a rare detailed characterisation of atrans-eQTL effect cascade from a proximalciseffect to the affected signalling pathway, transcription factor, and target genes. This highlights how co-expression analysis combined with functional enrichment analysis can greatly improve the identification and prioritisation oftrans-eQTLs when applied to emerging cell-type specific datasets.
Taking rapid and intermittent cocaine infusions enhances both incentive motivation for the drug and cocaine-induced gene regulation in corticostriatal regions
Authors: Minogianis Ellie-Anna , Samaha Anne-Noël 
Published: April 2020

ABSTRACTA goal in addiction research is to distinguish forms of neuroplasticity that are involved in the transition to addiction from those involved in mere drug taking. Animal models of drug self-administration are essential in this context. Here, we compared in male rats two cocaine self-administration procedures that differ in the extent to which they evoke addiction-like behaviours. We measured both incentive motivation for cocaine using progressive ratio procedures, and cocaine-induced c-fosmRNA expression, a marker of neuronal activity. Rats self-administered intravenous cocaine (0.25 mg/kg/infusion) for seven daily 6-hour sessions. One group had intermittent access (IntA; 6 minutes ON, 26 minutes OFF x 12) to rapid infusions (delivered over 5 seconds). This models the temporal kinetics of human cocaine use and produces robust addiction-like behaviour. The other group had Long access (LgA) to slower infusions (90 seconds). This produces high levels of intake without promoting robust addiction-like behaviour. LgA-90s rats took twice as much cocaine as IntA-5s rats did, but IntA-5s rats showed greater incentive motivation for the drug. Following a final self-administration session, we quantified c-fosmRNA expression in corticostriatal regions. Compared to LgA-90s rats, IntA-5s rats had more cocaine-induced c-fosmRNA in the orbitofrontal and prelimbic cortices and the caudate-putamen. Thus, a cocaine self-administration procedure (intermittent intake of rapid infusions) that promotes increased incentive motivation for the drug also enhances cocaine-induced gene regulation in corticostriatal regions. This suggests that increased drug-induced recruitment of these regions could contribute to the neural and behavioural plasticity underlying the transition to addiction.
Adaptation and Selection Shape Clonal Evolution During Residual Disease and Recurrence
Authors: Walens Andrea , Lin Jiaxing , Damrauer Jeffrey S. , Lupo Ryan , Newcomb Rachel , Fox Douglas B. , Mabe Nathaniel W. , Gresham Jeremy , De Buysscher Tristan , Kelkar Hemant , Mieczkowski Piotr A. , Owzar Kouros , Alvarez James V. 
Published: April 2020

SummaryThe survival of residual tumor cells following therapy and their eventual recurrence constitutes one of the biggest obstacles to obtaining cures in breast cancer, but it remains unclear how the clonal composition of tumors changes during tumor relapse. We used cellular barcoding to directly monitor clonal dynamics during tumor recurrence in a genetically engineered mouse model. We found that the clonal diversity of tumors progressively decreased during tumor regression, residual disease, and recurrence. Only a fraction of subclones survived oncogene withdrawal and persisted in residual tumors. The minimal residual disease phase itself was accompanied by a continued attrition of clones, suggesting an ongoing process of selection during dormancy. The reactivation of dormant residual cells into recurrent tumors followed several distinct evolutionary routes. Approximately half of the recurrent tumors exhibited a striking clonal dominance in which one or two subclones comprised the vast majority of the tumor. The majority of these clonal recurrent tumors exhibited evidence ofde novoacquisition of Met amplification, and were sensitive to small-molecule Met inhibitors. A second group of recurrent tumors exhibited marked polyclonality, with thousands of subclones and a clonal architecture very similar to primary tumors. These polyclonal recurrent tumors were not sensitive to Met inhibitors, but were instead dependent upon an autocrine IL-6 – Stat3 pathway. These results suggest that the survival and reactivation of dormant tumors can proceed via multiple independent routes, producing recurrent tumors with distinct clonal composition, genetic alterations, and drug sensitivities.
Pleiotropy-guided transcriptome imputation from normal and tumor tissues identifies new candidate susceptibility genes for breast and ovarian cancer
Authors: Kar Siddhartha P. , Considine Daniel P. C. , Tyrer Jonathan P. , Plummer Jasmine T. , Chen Stephanie , Dezem Felipe S. , Barbeira Alvaro N. , Rajagopal Padma S. , Rosenow Will , Antón Fernando M. , Bodelon Clara , Chang-Claude Jenny , Chenevix-Trench Georgia , deFazio Anna , Dörk Thilo , Ekici Arif B. , Ewing Ailith , Fountzilas George , Goode Ellen L. , Hartman Mikael , Heitz Florian , Hillemanns Peter , Høgdall Estrid , Høgdall Claus K. , Huzarski Tomasz , Jensen Allan , Karlan Beth Y. , Khusnutdinova Elza , Kiemeney Lambertus A. , Kjaer Susanne K. , Klapdor Rüdiger , Köbel Martin , Li Jingmei , Liebrich Clemens , May Taymaa , Olsson Håkan , Permuth Jennifer B. , Peterlongo Paolo , Radice Paolo , Ramus Susan J. , Riggan Marjorie J. , Risch Harvey A. , Saloustros Emmanouil , Simard Jacques , Szafron Lukasz M. , Thompson Cheryl L. , Vierkant Robert A. , Winham Stacey J. , Zheng Wei , Doherty Jennifer A. , Berchuck Andrew , Lawrenson Kate L. , Im Hae K. , Manichaikul Ani W. , Pharoah Paul D. P. , Gayther Simon A. , Schildkraut Joellen M. 
Published: April 2020

AbstractFamilial, genome-wide association (GWAS), and sequencing studies and genetic correlation analyses have progressively unraveled the shared or pleiotropic germline genetics of breast and ovarian cancer. In this study, we aimed to leverage this shared germline genetics to improve the power of transcriptome-wide association studies (TWAS) to identify candidate breast cancer and ovarian cancer susceptibility genes. We built gene expression prediction models using the PrediXcan method in 681 breast and 295 ovarian tumors from The Cancer Genome Atlas and 211 breast and 99 ovarian normal tissue samples from the Genotype-Tissue Expression project and integrated these with GWAS meta-analysis data from the Breast Cancer Association Consortium (122,977 cases/105,974 controls) and the Ovarian Cancer Association Consortium (22,406 cases/40,941 controls). The integration was achieved through novel application of a pleiotropy-guided conditional/conjunction false discovery rate approach for the first time in the setting of a TWAS. This identified 14 new candidate breast cancer susceptibility genes spanning 11 genomic regions and 8 new candidate ovarian cancer susceptibility genes spanning 5 genomic regions at conjunction FDR < 0.05 that were > 1 Mb away from known breast and/or ovarian cancer susceptibility loci. We also identified 38 candidate breast cancer susceptibility genes and 17 candidate ovarian cancer susceptibility genes at conjunction FDR < 0.05 at known breast and/or ovarian susceptibility loci. Overlaying candidate causal risk variants identified by GWAS fine mapping onto expression prediction models for genes at known loci suggested that the association for 55% of these genes was driven by the underlying GWAS signal.SignificanceThe 22 new genes identified by our cross-cancer analysis represent promising candidates that further elucidate the role of the transcriptome in mediating germline breast and ovarian cancer risk.
Ribosome profiling reveals ribosome stalling on tryptophan codons upon oxidative stress in fission yeast
Authors: Rubio Angela , Ghosh Sanjay , Mülleder Michael , Ralser Markus , Mata Juan 
Published: April 2020

ABSTRACTModulation of translation is an essential response to stress conditions. We have investigated the translational programmes launched by the fission yeastSchizosaccharomyces pombesubject to five environmental stresses: oxidative stress, heavy metal, heat shock, osmotic shock and DNA damage. We also explored the contribution of two major defence pathways to these programmes: The Integrated Stress Response, which directly regulates translation initiation, and the stress-response MAPK pathway. To obtain a genome-wide and high-resolution view of this phenomenon, we performed ribosome profiling of control cells and of cells subject to each of the five stresses mentioned above, both in wild type background and in cells in which the Integrated Stress Response or the MAPK pathway were inactivated.Translational changes were partially dependent on the integrity of both signalling pathways. Interestingly, we found that the transcription factor Fil1, a functional homologue of the Gcn4 and Atf4 proteins (from budding yeast and mammals, respectively), was highly upregulated in most stresses. Consistent with this result, Fil1 was required for the normal response to most stresses. A large group of mRNAs were translationally downregulated, including many required for ribosome biogenesis. Overall, our data suggest that severe stresses lead to the implementation of a universal translational response, which includes energy-saving measures (reduction of ribosome production) and induction of a Fil1-mediated transcriptional programme.Surprisingly, ribosomes stalled on tryptophan codons specifically upon oxidative stress, a phenomenon that is likely caused by a decrease in charged tRNA-Tryptophan. Tryptophan stalling led to a mild translation elongation reduction and contributed to the inhibition of initiation by the Integrated Stress Response. Taken together, our results show that different stresses elicit common and specific translational responses, revealing a special and so far unknown role in Tryptophan-tRNA availability.
TheSSU1checkup, a rapid tool for detecting chromosomal rearrangements of theSaccharomyces cerevisiaechromosome XVI. An ecological and technological study on wine yeast
Authors: Marullo Philippe , Claisse Olivier , Eder Maria Laura Raymond , Börlin Marine , Feghali Nadine , Bernard Margaux , Legras Jean-Luc , Albertin Warren , Rosa Alberto Luis , Masneuf-Pomarede Isabelle 
Published: April 2020

1)AbstractChromosomal rearrangements (CR) such as translocations, duplications and inversions play a decisive role in the adaptation of microorganisms to specific environments. In enologicalSaccharomyces cerevisiaestrains, CR involving the promoter region of the geneSSU1lead to a higher sulfite tolerance by enhancing the SO2efflux. To date, three differentSSU1associated CR events have been described, including translocations XV-t-XVI and VIII-t-XVI and inversion inv-XVI. In the present study, we developed a multiplex PCR method (SSU1check-up) that allows a rapid characterization of these three chromosomal configurations in a single experiment. Nearly 600S. cerevisiaestrains collected from fermented grape juice were genotyped by microsatellite markers. We demonstrated that alleles of theSSU1promoter are differently distributed according to the wine environment (cellar versus vineyard) and the nature of the grape juice. Moreover, rearrangedSSU1promoters are significantly enriched among commercial starters. In addition, nearly isogenic strains collected in similar environments show different CR suggesting that translocation events occur with a non-negligible frequency in clonal populations likely due to mitotic recombination events. Finally, the link between the nature ofSSU1promoter and the tolerance to sulfite was statistically validated in natural grape juice containing various SO2concentrations. TheSSU1check-up is therefore a convenient new tool for addressing population genetics questions and for selecting yeast strains by using molecular markers.
Structural and biochemical characterization of nsp12-nsp7-nsp8 core polymerase complex from COVID-19 virus
Authors: Peng Qi , Peng Ruchao , Yuan Bin , Zhao Jingru , Wang Min , Wang Xixi , Wang Qian , Sun Yan , Fan Zheng , Qi Jianxun , Gao George F. , Shi Yi 
Published: April 2020

SummaryThe ongoing global pandemic of coronavirus disease 2019 (COVID-19) has caused huge number of human deaths. Currently, there are no specific drugs or vaccines available for this virus. The viral polymerase is a promising antiviral target. However, the structure of COVID-19 virus polymerase is yet unknown. Here, we describe the near-atomic resolution structure of its core polymerase complex, consisting of nsp12 catalytic subunit and nsp7-nsp8 cofactors. This structure highly resembles the counterpart of SARS-CoV with conserved motifs for all viral RNA-dependent RNA polymerases, and suggests the mechanism for activation by cofactors. Biochemical studies revealed reduced activity of the core polymerase complex and lower thermostability of individual subunits of COVID-19 virus as compared to that of SARS-CoV. These findings provide important insights into RNA synthesis by coronavirus polymerase and indicate a well adaptation of COVID-19 virus towards humans with relatively lower body temperatures than the natural bat hosts.
Cloning and functional expression of a food-grade circular bacteriocin, plantacyclin B21AG, in probioticLactobacillus plantarumWCFS1
Authors: Gor Mian Chee , Golneshin Aida , Van Thi Thu Hao , Moore Robert J. , Smith Andrew T. 
Published: April 2020

AbstractThere is an increasing consumer demand for minimally processed, preservative free and microbiologically safe food. These factors, combined with risks of antibiotic resistance, have led to interest in bacteriocins produced by lactic acid bacteria (LAB) as natural food preservatives and as protein therapeutics. We previously reported the discovery of plantacyclin B21AG, a novel circular bacteriocin produced byLactobacillus plantarumB21. Here, we describe the cloning and functional expression of the bacteriocin gene cluster in the probioticLactobacillus plantarumWCFS1. Genome sequencing demonstrated that the bacteriocin is encoded on a 20 kb native plasmid, designated as pB21AG01. Seven open reading frames (ORFs) putatively involved in bacteriocin production, secretion and immunity were cloned into anE. coli/Lactobacillusshuttle vector, pTRKH2. The resulting plasmid, pCycB21, was transformed intoL. plantarumWCFS1. The cell free supernatants (CFS) of both B21 and WCFS1 (pCycB21) showed an antimicrobial activity of 800 AU/mL when tested against the WCFS1 (pTRKH2) indicator strain, indicating functional expression of plantacyclin B21AG. Real-time PCR analysis revealed that the relative copy number of pB21AG01 was 7.60 ± 0.79 inL. plantarumB21 whilst pCycB21 and pTRKH2 was 0.51 ± 0.05 and 25.19 ± 2.68 copies, respectively in WCFS1. This indicates that the bacteriocin gene cluster is located on a highly stable, low copy number plasmid pB21AG01 inL. plantarumB21. Inclusion of the native promoter for the bacteriocin operon from pB21AG01 may result in similar inhibitory zones observed in both wild type and recombinant hosts despite the low copy number of pCycB21.
PAC-mediated AKI protection is critically mediated but does not exclusively depend on cell-derived microvesicles
Authors: Dihazi H. , Schwarze K. , Patschan S. , Müller G.A. , Ritter O. , Patschan D. 
Published: April 2020

AbstractAcute Kidney Injury (AKI) significantly worsens the prognosis of hospitalized patients. In recent years, cell-based strategies have been established as reliable option for improving AKI outcomes in experimental AKI. Own studies focused on so-called Proangiogenic Cells (PACs). Mechanisms that contribute to PAC-mediated AKI protection include production / secretion of extracellular vesicles (MV - microvesicles). In addition, the cells most likely act by paracrinic processes (secretome). The current study evaluated whether AKI may be preventable by the administration of either PAC-derived MV and / or the secretome alone. AKI was induced in male C57/Bl6N mice (8-12 weeks) by bilateral renal ischemia (IRI - 40 minutes). Syngeneic murine PACs were stimulated with either melatonine, Angiopoietin-1 or -2, or with Bone Morphogenetic Protein-5 (BMP-5) for one hour, respectively. PAC-derived MV and the vesicle-depleted supernatant were subsequently collected and i.v. injected post-ischemia. Mice were analyzed 48 hours later. IRI induced significant kidney excretory dysfunction as reflected by higher serum cystatin C levels. The only measure that improved AKI was the injection of MV, collected from native PACs. The following conditions worsened post-ischemic renal function even further: MV+Ang-1, MV+BMP-5, MV+melatonin, and MV+secretome+Ang-1. Together, our data show that PAC-mediated AKI protection substantially depends on the availability of cell-derived MV. However, since previous data showed improved AKI-protection by PACs after cell preconditioning with certain mediators (Ang-1 and -2, melatonine, BMP-5), other than exclusively vesicle-dependent mechanisms must be involved in PAC-mediated AKI protection.
Pairing your Sox: Identification of Sox11 partner proteins and interaction domains in the developing neural plate
Authors: Singleton Kaela S. , Silva-Rodriguez Pablo , Silva Elena M. 
Published: April 2020

AbstractSox11, a member of the SoxC family of transcription factors, has distinct functions at different times in neural development. Studies in mouse, frog, chick and zebrafish show that Sox11 promotes neural fate, neural differentiation, and neuron maturation in the central nervous system. These diverse roles are controlled in part by spatial and temporal-specific protein interactions. However, the partner proteins and Sox11-interaction domains underlying these diverse functions are not well defined. Here, we identify partner proteins and the domains ofXenopusSox11(xSox11) required for protein interaction and function during neurogenesis. Our data show that Sox11 co-localizes and interacts with Pou3f2 and Ngn2 in the anterior neural plate and in early neurons, respectively. We also demonstrate that xSox11 does not interact with Ngn1, a high affinity partner of Sox11 in the mouse cortex, suggesting that Sox11 has species-specific partner proteins. Additionally, we determined that the N-terminus including the HMG domain of xSox11 is necessary for interaction with Pou3f2 and Ngn2, and established a novel role for the N-terminal 46 amino acids in the establishment of placodal progenitors. This is the first identification of partner proteins forXenopusSox11 and of domains required for partner protein interactions and distinct roles in neurogenesis.
Industry expectations for beginning agricultural lenders
Authors: Hanson Erik , Wachenheim Cheryl Joy 
Published: April 2020

PurposeThis paper aims to describe the nature of an agricultural lending position and reports an industry perspective of skills required for a new graduate entering the profession.Design/methodology/approachLoan officers and those directly supervising loan officers were surveyed regarding job characteristics and perceptions of the skills needed for career success.FindingsLenders perceive on-the-job training to be slightly more valuable than post-secondary training for preparing students for a career in agricultural lending. Financial skills were rated to be roughly as important as non-financial skills for early career success. Financial topics identified as important include financial statements, breakeven analysis and accrual-basis earnings. Communication and risk analysis were rated as the most important non-financial topics needed for early career success. Regarding their jobs, lenders indicated that they devote much of their time to managing loans and developing or maintaining relationships with customers. Benefits were identified as the most important feature for job satisfaction, particularly among agricultural lenders, that also work essentially full time on a farm or ranch. Work environment, work flexibility, location and salary were also considered to be important job characteristics.Originality/valueThis paper updates the literature regarding industry's preferred skills and refines the surveyed audience to only those currently performing or directly supervising agricultural lending. It adds a unique perspective on the work time allocated to various agricultural lending activities and lenders' valuation of job characteristics. These insights may guide curricular and course design, career planning and employee recruitment and marketing efforts.
The effect of innovative food products on shaping the image of their offerors
Authors: Baruk Agnieszka Izabela , Białoskurski Sebastian 
Published: April 2020

PurposeThe main purpose of this article is to determine the significance of selected reasons for the market success of a new food product depending on the perception of the offeror.Design/methodology/approachA cognitive-critical analysis of the literature on marketing, innovation management and image management were used to prepare the theoretical section. The results of the analysis indicate a cognitive and research gap regarding the role of innovative food products in creating their offerors' image. In order to reduce the gap, empirical studies were conducted on a sample of young Polish consumers, in which a questionnaire was used to gather primary data. The data were subjected to statistical analysis using the following methods and statistical tests: exploratory factor analysis, Kruskal–Wallis test, Pearson chi-square independence test and V-Cramer coefficient analysis.FindingsThe results of the analysis conducted indicated, inter alia, that there are no statistically significant dependencies between opinions on the importance of individual components to achieve market success by a new food product (NFP), and on the relationship between the perception of the NFP and the image of the offeror. Opinions on the impact of an offeror's image on the perception of an NFP are a feature that differentiates the factors indicating the success of NFPs in the case of three variables only.Originality/valueThe results obtained from the research have a cognitive and applicability value, characterized by originality. Until now, the role of innovative food products in creating their offerors' image has not been analyzed.