bluuebunny/crossref_metadata_2025 huggingface dataset:
Detection of Tuberculosis by The Analysis of Exhaled Breath Particles with High-resolution Mass Spectrometry
Authors: Chen Dapeng , Bryden Wayne A. , Wood Robin
Published: April 2020

Tuberculosis remains a global health threat killing over 1 million peopleperyear. Current sputum-based diagnostics are specific but lack sensitivity resulting in treatment of many sputum negative cases. In this proof-of-concept study, we used high-resolution mass spectrometry to identify specific lipids in peripheral lung fluid samples of TB patients and controls, captured using a novel non-invasive sampling system. Exhaled respiratory particles were collected in liquid and after concentration and lipid extraction directly infused into a high-resolution mass spectrometer. High-resolution mass spectrometric data collection was conducted in a dual ion mode and chemical compositions were constructed using accurate mass measurement. Over 400 features with high segregating capacity were extracted and optimized using feature selection algorithm and machine learning, from which the accuracy of detection of positive tuberculosis patients was estimated. This current strategy provides sensitivity offered by high-resolution mass spectrometry and can be readily susceptible for developing a novel clinical assay exploring peripheral lung fluid for the detection of active TB cases.
Convergent evolution of p38/MAPK activation in hormone resistant prostate cancer mediates pro-survival, immune evasive, and metastatic phenotypes
Authors: Ware Kathryn E. , Gupta Santosh , Eng Jared , Kemeny Gabor , Puviindran Bhairavy J. , Foo Wen-Chi , Crawford Lorin A. , Garland Almquist R. , Runyambo Daniella , Thomas Beatrice C. , Sheth Maya U. , Agarwal Anika , Pierobon Mariaelena , Petricoin Emanuel F. , Corcoran David L. , Freedman Jennifer , Patierno Steven R. , Zhang Tian , Gregory Simon , Sychev Zoi , Drake Justin M. , Armstrong Andrew J. , Somarelli Jason A.
Published: April 2020

Adaptation of cancer cells to targeted therapy follows ecological paradigms observed in natural populations that encounter resource depletion and changing environments, including activation of pro-survival mechanisms, migration to new locations, and escape of predation. We identified the p38 MAPK pathway as a common molecular driver of these three responses during the adaptation to hormone therapy resistance in prostate cancer. The p38 pathway is activated in therapy-resistant cells and mechanistically drives these three convergent responses through sustained AR activity, enhanced invasion and metastasis, and immune evasion. Targeting p38 signaling may represent a new therapeutic strategy to treat men with metastatic, hormone therapy-resistant prostate cancer.
Anti-EGFR Fibronectin Bispecific Chemically Self-Assembling Nanorings (CSANs) Induce Potent T cell Mediated Anti-Tumor Response and Downregulation of EGFR Signaling and PD-1/PD-L1 Expression
Authors: Kilic Ozgun , de Souza Marcos R. Matos , Almotlak Abdulaziz A. , Siegfried Jill M. , Wagner Carston R.
Published: April 2020

Numerous approaches have targeted the Epidermal Growth Factor Receptor (EGFR) for the development of anti-cancer therapeutics, since it is over-expressed on a variety of cancers. Recently, αEGFR chimeric antigen receptor (CAR)-T cells have shown potential promise for the immunological control of tumors. Our laboratory has recently demonstrated that bispecific chemically self-assembled nanorings (CSANs) can modify T cell surfaces and function as prosthetic antigen receptors (PARs). This technology allows selective targeting of tumor antigens due to high avidity of the multimeric rings, while incorporating a mechanism to dissociate the rings to prevent further T cell stimulation. Previously, PARs with single-chain variable fragments (scFvs) have been successfulin vitroandin vivo, activating T cells selectively at the tumor site. Alternatively, here we report fibronectin (FN3)-based PARs with improved properties such as increased protein yield, rapid protein production, increased protein stability and predicted low immunogenicity due to the human origin of fibronectins. We examined the cytotoxicity of EGFR-targeting PARsin vitroin which the affinities of the αEGFR fibronectins, the αEGFR/ αCD3 valency of the CSANs and the antigen expression levels were varied. Based on these selectivein vitrocytotoxicity results, we conducted anin vivostudy of FN3-PARs using an orthotopic breast cancer model. The FN3-PARs demonstrated potent tumor growth suppression with no adverse effects. Furthermore, these results demonstrated that FN3-PARs modulated the tumor microenvironment by downregulating EGFR signaling resulting in decreased PD-L1 expression. In addition, the expression of PD-1 was also found to be reduced. Collectively, these results demonstrate that FN3-PARs have the potential to direct selective T cell targeted tumor killing and that αEGFR FN3-PARs may enhance anti-tumor T cell efficacy by modulating the tumor microenvironment.
Tension causes structural unfolding of intracellular intermediate filaments
Authors: Fleissner Frederik , Kumar Sachin , Klein Noreen , Wirth Daniel , Dhiman Ravi , Schneider Dirk , Bonn Mischa , Parekh Sapun H.
Published: April 2020

Intermediate filament (IF) proteins are a class of proteins that constitute different filamentous structures in mammalian cells. As such, IF proteins are part of the load-bearing cytoskeleton and support the nuclear envelope. Molecular dynamics simulations have shown that IF proteins undergo secondary structural changes to compensate mechanical loads, which has been confirmed by experimentalin vitrostudies on IF hydrogels. However, the structural response of intracellular IF to mechanical load has yet to be elucidatedin cellulo. Here, we usein situnonlinear Raman imaging combined with multivariate data analysis to quantify the intracellular secondary structure of the IF cytoskeletal protein vimentin under different states of cellular tension. We find that cells under native cellular tension contain more unfolded vimentin than chemically or physically relaxed specimens. This indicates that unfolding of IF proteins occurs intracellularly when sufficient forces are applied, suggesting that IF structures act as local force sensors in the cell to mark locations under large mechanical tension.
Local adaptation ofLegionella pneumophilawithin a hospital hot water system increases tolerance to copper
Authors: Bédard Emilie , Trigui Hana , Liang Jeffrey , Doberva Margot , Paranjape Kiran , Lalancette Cindy , Faucher Sebastien P. , Prévost Michèle
Published: April 2020

In large-building water systems,Legionella pneumophilais exposed to common environmental stressors such as copper. The aim of this study was to evaluate the susceptibility to copper ofL. pneumophilaisolates recovered from various sites: two clinical and seven environmental from hot water systems biofilm & water, and from cooling tower water. After one-week acclimation in simulated drinking water, strains were exposed to various copper concentrations (0.8 to 5 mg/L) for over 672 hours. Complete loss of culturability was observed for three isolates, following copper exposure to 5 mg/L for 672h. Two ST1427-like isolates were highly sensitive to copper, while the other two, isolated from biofilm samples, were resistant. The expression of the copper resistance genecopAevaluated by RT-qPCR was significantly higher for the biofilm isolates. All four ST1427-like isolates were recovered from the same water system during an outbreak. Whole genome sequencing results confirmed that the four isolates are very close phylogenetically, differing by only 29 single nucleotide polymorphisms, suggestingin situadaptation to microenvironmental conditions, possibly due to epigenetic regulation. These results indicate that the immediate environment within a building water distribution system influences the tolerance ofL. pneumophilato copper. Increased contact ofL. pneumophilabiofilm strains with copper piping or copper alloys in the heat exchanger might lead to local adaptation. The phenotypic differences observed between water and biofilm isolates from the hot water system of a healthcare facility warrants further investigation to assess the relevance of evaluating disinfection performances based on water sampling alone.

Importance

Legionella pneumophilais a pathogen indigenous to natural and large building water systems in the bulk and the biofilm phases. The immediate environment within a system can impact the tolerance ofL. pneumophilato environmental stressors, including copper. In healthcare facilities, copper levels in water can vary, depending on water quality, plumbing materials and age. This study evaluated the impact of the isolation site (water vs biofilm, hot water system vs cooling tower) within building water systems. Closely related strains isolated from a healthcare facility hot water system exhibited variable tolerance to copper stress shown by differential expression ofcopA, with biofilm isolates displaying highest expression and tolerance. Relying on the detection ofL. pneumophilain water samples following exposure to environmental stressor such as copper may underestimate the prevalence ofL. pneumophila, leading to inappropriate risk management strategies and increasing the risk of exposure for vulnerable patients.
Area-specific Biased Global Efficiency in Functional Connectivity Provides Features Negatively Correlated with Age
Authors: Akama Hiroyuki , Ota Airi
Published: April 2020

It has been acknowledged that graph-theoretical coefficients computed from the adjacency matrix of cerebral resting-state functional connectivity (RSFC) represent aging of the brain and its plasticity facilitating cognitive reserve. In particular, global efficiency (GE) has been recognized as a crucial graph index for age-dependent RSFC. Using the dataset of the Nathan Kline Institute-Rockland Sample [NKI-RS], we found that the regions of the brain in which GE values decay with age were located in the subcortical zone and the cerebellum, whereas an opposite relationship was found in many frontal and parietal regions. Based on this systematic tendency, a new coefficient was proposed that corrects GE, referred to as biased GE (BGE); BGE is calculated by changing the sign of the weight between the superior and the inferior parts of the brain before separately averaging the respective sign groups of area-specific corrected GE values, to influence the raw global network GE. The BGE showed a significant negative correlation with age, irrespective of the scan condition, and strong consistency as an information source of a subject’s identity. We propose that this new index could play an important role in the clinical context of preventive medicine and the maintenance of healthy brains.
Structural basis for PRC2 decoding of active histone methylation marks H3K36me2/3
Authors: Finogenova Ksenia , Bonnet Jacques , Poepsel Simon , Schäfer Ingmar B. , Finkl Katja , Schmid Katharina , Litz Claudia , Strauss Mike , Benda Christian , Müller Jürg
Published: April 2020

Repression of genes by Polycomb requires that PRC2 modifies their chromatin by trimethylating lysine 27 on histone H3 (H3K27me3). At transcriptionally active genes, di- and trimethylated H3K36 inhibit PRC2. Here, the cryo-EM structure of PRC2 on dinucleosomes reveals how binding of its catalytic subunit EZH2 to nucleosomal DNA orients the H3 N-terminus via an extended network of interactions to place H3K27 into the active site. Unmodified H3K36 occupies a critical position in the EZH2-DNA interface. Mutation of H3K36 to arginine or alanine inhibits H3K27 methylation by PRC2 on nucleosomesin vitro. Accordingly,DrosophilaH3K36A and H3K36R mutants show reduced levels of H3K27me3 and defective Polycomb repression of HOX genes. The relay of interactions between EZH2, the nucleosomal DNA and the H3 N-terminus therefore creates the geometry that permits allosteric inhibition of PRC2 by methylated H3K36 in transcriptionally active chromatin.
Investigating regions of shared genetic variation in attention deficit/hyperactivity disorder and major depressive disorder: A GWAS meta-analysis
Authors: Powell Victoria , Martin Joanna , Thapar Anita , Rice Frances , Anney Richard J. L.
Published: April 2020

Attention deficit/hyperactivity disorder (ADHD) demonstrates a high level of comorbidity with major depressive disorder (MDD). One possible contributor to this is that the two disorders show high genetic correlation. However, the specific regions of the genome that may be responsible for this overlap are unclear. To identify variants associated with both ADHD and MDD, we performed a meta-analysis of GWAS of ADHD and MDD. All genome wide significant (p=5×10−8) SNPs in the meta-analysis that were also strongly associated (p=5×10−4) independently with each disorder were followed up. These putatively pleiotropic SNPs were tested for additional associations across a broad range of phenotypes. Fourteen linkage disequilibrium-independent SNPs were identified that were associated with each disorder separately (p=5×10−4) and in the cross-disorder meta-analysis (p=5×10−8). Nine of these SNPs had not been reported previously in either individual GWAS and can be considered as novel signals. Evidence supported nine of the fourteen SNPs acting as eQTL and two of the SNPs as brain eQTL. Index SNPs and their genomic regions demonstrated associations with other mental health phenotypes. Through conducting meta-analysis on ADHD and MDD only, our results build upon the previously observed genetic correlation between ADHD and MDD and reveal novel regions of the genome that may be implicated in this overlap.
Co-expression analysis reveals interpretable gene modules controlled bytrans-acting genetic variants
Authors: Kolberg Liis , Kerimov Nurlan , Peterson Hedi , Alasoo Kaur
Published: April 2020

Background

Developing 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.

Results

We 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.

Conclusions

Our 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

A 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

The 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

Familial, 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.

Significance

The 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

Modulation 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)

Chromosomal 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

The 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

There 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

Acute 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

Sox11, 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.
The Kinase-Dependent and Independent Functions of Cdk4 and Cdk6 Regulate Continuous Proliferation and the Exit From Quiescence Differently
Authors: Nataraj Sarah E. , Blain Stacy W.
Published: April 2020

Cdk4 and cdk6 have long been considered functional homologues, despite the fact that tissue-specific differences are detected in the single cdk4 or cdk6 knockout animals. To explore the role of cdk4 and cdk6 in the same model system, we overexpressed variants of cdk4 and cdk6 in Mv1Lu cells to determine their effect on cell cycle progression. We found that cells that overexpressed cdk4 were able to reenter the cell cycle from a contact arrested quiescent state in a kinase-dependent fashion, consistent with the role of this kinase in G0-G1 phase exit. However, we also found that expression of catalytically inactive variants of cdk6 accelerated G0 release, enabled the cell to overcome TGF-β-mediated growth arrest, proliferate in the absence of cyclin D-associated kinase activity and maintain cdk2 activity, while cells expressing catalytically inactive cdk4 were not. This suggested that cdk6 expression was able to affect cell cycle progression in a kinase-independent manner that was distinct from the actions of cdk4. Cdk4 appears unable to associate with cyclin D in the absence of a required assembly factor, such as p27Kip1, but, by gel filtration chromatography, we detected the presence of a previously unidentified, catalytically inactive cyclin D-cdk6 dimer, which might contribute to the kinase-independent, pro-proliferative activity of cdk6.
Fast and accurate defocus modulation for improved tunability of cryo-EM experiments
Authors: Danev Radostin , Iijima Hirofumi , Matsuzaki Mizuki , Motoki Sohei
Published: April 2020

Current data collection strategies in electron cryo-microscopy (cryo-EM) record multiframe movies with static optical settings. This limits the number of adjustable parameters that can be used to optimize the experiment. Here, a method for fast and accurate defocus (FADE) modulation during movie acquisition is proposed. It uses the objective lens aperture as an electrostatic pole that locally modifies the electron beam potential. The beam potential variation is converted to defocus change by the typically undesired chromatic aberration of the objective lens. The simplicity, electrostatic principle and low electrical impedance of the device allow fast switching speeds that will enable per-frame defocus modulation of cryo-EM movies. Researchers will be able to define custom defocus `recipes' and tailor the experiment for optimal information extraction from the sample. The FADE method could help to convert the microscope into a more dynamic and flexible optical platform that delivers better performance in cryo-EM single-particle analysis and electron cryo-tomography.
A five-coordinate cobalt bis(dithiolene)–phosphine complex [Co(pdt)2(PTA)] (pdt = phenyldithiolene; PTA = 1,3,5-triaza-7-phosphaadamantane)
Authors: Williams DaShawn , Brannon Jacob P. , Chandrasekaran Perumalreddy , Stieber S. Chantal E.
Published: April 2020

The title compound, bis(1,2-diphenyl-2-sulfanylideneethanethiolato-κ2
S,S′)(1,3,5-triaza-7-phosphaadamantane-κP)cobalt(II) dichloromethane hemisolvate, [Co(pdt)2(PTA)]·0.5C2H4Cl2 or [Co(C14H10S2)2(C6H12N3P)]·0.5C2H4Cl2, contains two phenyldithiolene (pdt) ligands and a 1,3,5-triaza-7-phosphaadamantane (PTA) ligand bound to cobalt with the solvent 1,2-dichloroethane molecule located on an inversion center. The cobalt core exhibits an approximately square-pyramidal geometry with partially reduced thienyl radical monoanionic ligands. The supramolecular network is consolidated by hydrogen-bonding interactions primarily with nitrogen, sulfur and chlorine atoms, as well as parallel displaced π-stacking of the aryl rings. The UV–vis, IR, and CV data are also consistent with monoanionic dithiolene ligands and an overall CoII oxidation state.
Industry expectations for beginning agricultural lenders
Authors: Hanson Erik , Wachenheim Cheryl Joy
Published: April 2020

Purpose

This 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/approach

Loan officers and those directly supervising loan officers were surveyed regarding job characteristics and perceptions of the skills needed for career success.

Findings

Lenders 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/value

This 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

Purpose

The 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/approach

A 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.

Findings

The 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/value

The 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.
Reward-based epigenetic learning algorithm for a decentralised multi-agent system
Authors: Mukhlish Faqihza , Page John , Bain Michael
Published: April 2020

Purpose

This paper aims to propose a novel epigenetic learning (EpiLearn) algorithm, which is designed specifically for a decentralised multi-agent system such as swarm robotics.

Design/methodology/approach

First, this paper begins with overview of swarm robotics and the challenges in designing swarm behaviour automatically. This should indicate the direction of improvements required to enhance an automatic swarm design. Second, the evolutionary learning (EpiLearn) algorithm for a swarm system using an epigenetic layer is formulated and discussed. The algorithm is then tested through various test functions to investigate its performance. Finally, the results are discussed along with possible future research directions.

Findings

Through various test functions, the algorithm can solve non-local and many local minima problems. This article also shows that by using a reward system, the algorithm can handle the deceptive problem which often occurs in dynamic problems. Moreover, utilization of rewards from the environment in the form of a methylation process on the epigenetic layer improves the performance of traditional evolutionary algorithms applied to automatic swarm design. Finally, this article shows that a regeneration process that embeds an epigenetic layer in the inheritance process performs better than a traditional crossover operator in a swarm system.

Originality/value

This paper proposes a novel method for automatic swarm design by taking into account the importance of multi-agent settings and environmental characteristics surrounding the swarm. The novel evolutionary learning (EpiLearn) algorithm using an epigenetic layer gives the swarm the ability to perform co-evolution and co-learning.
Sustainability in management education: a Biggs’ 3P model application
Authors: Kanashiro Patricia , Iizuka Edson Sadao , Sousa Caio , Dias Suzi Elen FeRReira
Published: April 2020

Purpose

The purpose of this paper is to assess the main factors that contribute to teaching and learning sustainability in management education (SiME), which is defined as a body of knowledge that meets the needs of both current and future generations of students.

Design/methodology/approach

The authors adopt the Biggs’ Presage–Process–Product (3P) learning model to guide and categorize the findings from the literature review on SiME. This study provides an overview of journal articles published between 2002 and 2017.

Findings

In the context of SiME, Biggs’ 3P model shows how teaching context and students’ background (presage factors) influence students’ approaches to learning, which can range from surface to deep learning (process) and result in various learning outcomes (products).

Research limitations/implications

The literature review may have excluded important and relevant work from the sample.

Practical implications

This review highlights that personal and institutional commitments are necessary to promote effective learning of sustainability.

Social implications

Effective learning outcomes (deep learning) in sustainability should encourage students to reflect on their personal values and behaviors and to acquire analytical skills aimed at promoting conservation and remediation of social, environmental and economic problems.

Originality/value

This paper provides an application of Biggs’ 3P learning model in the context of sustainability, which highlights the conditions for deep learning as critical given the complexity and urgency of addressing sustainability crises.
Factors affecting consumers' pro-environmental behaviour in nutricosmetics consumption: the role of perceived environmental responsibility as a mediator
Authors: Shahrin Ruzanna , Quoquab Farzana , Mohammad Jihad , Jamil Rossilah
Published: April 2020

Purpose

This study aims to examine the direct effect of compensatory health beliefs (CHBs), environmental self-identity and perceived environmental responsibility (PER) towards consumers' pro-environmental behaviour (PEB). Moreover, this study also investigates the mediating role of PER.

Design/methodology/approach

Data were collected from nutricosmetics consumers in Malaysia. A questionnaire survey was carried out in three major shopping complexes in Klang Valley areas, which generated 448 completed usable responses. The partial least square technique (SmartPLS, version 3) was used to analyse the data and to test the study hypotheses.

Findings

The results revealed that CHBs, environmental self-identity and environmental perceived responsibility positively affect consumers’ PEB in nutricosmetics consumption. Additionally, data supported the mediating role of PER in the relationship between CHB, environmental self-identity and PEB.

Practical implications

It is expected that the study findings will provide significant insights to help marketers and policymakers about consumers’ nutricosmetic products consumption. It will help the marketers to plan for effective marketing strategies to produce environmentally friendly products and to serve the green consumer segment effectively. Moreover, companies attempting to launch new nutricosmetics brands may find the results helpful in understanding PEB.

Originality/value

This study is among the pioneers to examine consumers’ PEB of nutricosmetics products. Moreover, there is a dearth of studies that have investigated the PEB of consumers in regard to the CHBs, environmental self-identity and PER towards nutricosmetics consumption. Additionally, this study examines the mediating role of PER between “CHBs and PEB” and “environmental self-identity and PEB”, which are yet to examine in the past literature in the field.