bluuebunny/crossref_metadata_2025 huggingface dataset:
MicroRNA-148a Regulates Low-Density Lipoprotein Metabolism by Repressing the (Pro)renin Receptor
Authors: Wang Na , He Lishu , Lin Hui , Tan Lunbo , Sun Yuan , Zhang Xiaoying , Danser A.H. Jan , Lu Hong S. , He Yongcheng , Lu Xifeng
Published: November 2019

High plasma LDL cholesterol (LDL-c) concentration is a major risk factor for atherosclerosis. Hepatic LDLR regulates LDL metabolism, and thereby plasma LDL-c concentration. Recently, we identified the (pro)renin receptor [(P)RR] as a novel regulator of LDL metabolism, which regulates LDLR degradation and hence its protein abundance and activity. In silicon analysis suggests that the (P)RR is a target of miR-148a. In this study we determined whether miR-148a could regulate LDL metabolism by regulating (P)RR expression in HepG2 and Huh7 cells. We found that miR-148a suppressed (P)RR expression by binding to the 3’-untranslated regions (3’-UTR) of (P)RR mRNA. Mutating the binding sites for miR-148a in the 3’-UTR of (P)RR mRNA abolished the inhibitory effects of miR-148a on (P)RR expression. In line with our recent findings, reduced (P)RR expression resulted in decreased cellular LDL uptake, likely as a consequence of decreased LDLR protein abundance. Overexpressing the (P)RR prevented miR-148a-induced reduction in LDLR abundance and cellular LDL uptake. Our study supports a new concept that miR-148a is a regulator of (P)RR expression. By reducing (P)RR abundance, miR-148a decreases LDLR protein abundance and consequently cellular LDL uptake.
Evaluating the effects of arousal and emotional valence on performance of racing greyhounds
Authors: Starling Melissa , Spurrett Anthony , McGreevy Paul
Published: November 2019

The racing greyhound industry in Australia has come under scrutiny in recent years due to animal welfare concerns, including so-called behavioural wastage whereby physically sound greyhounds are removed from the racing industry because of poor performance. The non-medical reasons why greyhounds perform poorly at the racetrack are not well understood, but may include insufficient reinforcement for racing, or negative affective states associated with the context of racing. This study sought evidence for the affective states of greyhounds (n=525) at race meets and associations of those states with performance. It collected demographic, behavioural and performance data, along with infrared thermographic images of greyhounds at race-meets to investigate whether arousal influenced performance. It also collected behavioural data in the catching pen at the completion of races to examine possible evidence of frustration that may reflect sub-optimal behavioural reinforcement.

Linear regression models were built to determine factors affecting greyhound performance. Increasing mean eye temperature after the race and increasing greyhound age both had a statistically significant, negative effect on performance. The start box number also had a significant effect, with boxes 4, 5 and 7 having a negative effect on performance. There was a significant effect of track on mean eye temperatures before and after the race, suggesting that some tracks may be inherently more stressful for greyhounds than others. Behaviours that may indicate frustration in the catching pen were extremely common at two tracks, but much less common at the third, where play objects in motion were used to draw greyhounds into the catching pen. The study provides evidence for the use of eye temperature in predicting performance, guidance for assessment of poor performance in greyhounds and suggested approaches to the management of frustration in racing greyhounds.
The novel microRNAs hsa-miR-nov7 and hsa-miR-nov3 are over-expressed in locally advanced breast cancer
Authors: Poduval Deepak , Sichmanova Zuzana , Straume Anne Hege , Lønning Per Eystein , Knappskog Stian
Published: November 2019

miRNAs are an important class of small non-coding RNAs, which play a versatile role in gene regulation at the post-transcriptional level. Expression of miRNAs is often deregulated in human cancers.

We analyzed small RNA massive parallel sequencing data from 50 locally advanced breast cancers aiming to identify novel breast cancer related miRNAs. We successfully predicted 10 novel miRNAs, out of which 2 (hsa-miR-nov3 and hsa-miR-nov7) were recurrent. Applying high sensitivity qPCR, we detected these two microRNAs in 206 and 214 out of 223 patients in the study from which the initial cohort of 50 samples were drawn. We found hsa-miR-nov3 and hsa-miR-nov7 both to be overexpressed in tumor versus normal breast tissue in a separate set of 13 patients (p=0.009 and p=0.016, respectively) from whom both tumor tissue and normal tissue were available. We observedhsa-miR-nov3to be expressed at higher levels in ER-positive compared to ER-negative tumors (p=0.037). Further stratifications revealed particularly low levels in the her2-like and basal-like cancers compared to other subtypes (p=0.009 and 0.040, respectively).

We predicted target genes for the 2 microRNAs and identified inversely correlated genes in mRNA expression array data available from 203 out of the 223 patients. Applying the KEGG and GO annotations to target genes revealed pathways essential to cell development, communication and homeostasis.

Although a weak association between high expression levels ofhsa-miR-nov7and poor survival was observed, this did not reach statistical significance.hsa-miR-nov3expression levels had no impact on patient survival.
Hyperglycemia enhances cancer immune evasion by inducing alternative macrophage polarization through increased O-GlcNAcylation
Authors: Mantuano Natália Rodrigues , Stanczak Michal A. , de Araújo Oliveira Isadora , Kirchhammer Nicole , Filardy Alessandra , Monaco Gianni , Santos Ronan Christian , Fonseca Agatha Carlos , Fontes Miguel , de Souza Bastos César , Dias Wagner B. , Zippelius Alfred , Todeschini Adriane R. , Läubli Heinz
Published: November 2019

Diabetes mellitus (DM) significantly increases the risk for cancer and cancer progression. Hyperglycemia is the defining characteristic of DM and tightly correlates with a poor prognosis in cancer patients. The hexosamine biosynthetic pathway (HBP) is emerging as a pivotal cascade linking high glucose, tumor progression and impaired immune function. Here we show that enhanced glucose flow through the HBP drives cancer progression and immune evasion by increasing O-GlcNAcylation in tumor-associated macrophages (TAMs). Increased O-GlcNAc skewed macrophage polarization to a M2-like phenotype. HBP or O-GlcNAcylation inhibition reprogrammed TAMs to an anti-tumoral phenotype. Finally, we found an upregulation of M2 markers on TAMs in DM2 patients with colorectal cancer compared to non-diabetic normoglycemic patients. Our results provide evidence for a new and targetable mechanism of cancer immune evasion in patients with hyperglycemia, advocating for strict control of hyperglycemia in cancer patients.

Significance

Hyperglycemia increases O-GlcNAc levels in TAMs, programing them to a pro-tumorigenic phenotype (M2-like), contributing to cancer progression. Inhibition of O-GlcNAcylation could therefore be used to reprogram intratumoral macrophages to an anti-tumoral phenotype.
Asymmetrical reliability of the Alda Score favours a dichotomous representation of lithium responsiveness
Authors: Nunes Abraham , Trappenberg Thomas , Alda Martin
Published: November 2019

The Alda score is commonly used to quantify lithium responsiveness in bipolar disorder. Most often, this score is dichotomized into “responder” and “non-responder” categories, respectively. This practice is often criticized as inappropriate, since continuous variables are thought to invariably be “more informative” than their dichotomizations. We therefore investigated the degree of informativeness across raw and dichotomized versions of the Alda score, using data from a published study of the scale’s inter-rater reliability (n=59 raters of 12 standardized vignettes each). After learning a generative model for the relationship between observed and ground truth scores (the latter defined by a consensus rating of the 12 vignettes), we show that the dichotomized scale is more robust to inter-rater disagreement than the raw 0-10 scale. Further theoretical analysis shows that when a measure’s reliability is stronger at one extreme of the continuum—a scenario which has received little-to-no statistical attention, but which likely occurs for the Alda score ≥ 7—dichotomization of a continuous variable may be more informative concerning its ground truth value, particularly in the presence of noise. Our study suggests that research employing the Alda score of lithium responsiveness should continue using the dichotomous definition, particularly when data are sampled across multiple raters.
Using structural connectivity to augment community structure in EEG functional connectivity
Authors: Glomb Katharina , Mullier Emeline , Carboni Margherita , Rubega Maria , Iannotti Giannarita , Tourbier Sebastien , Seeber Martin , Vulliemoz Serge , Hagmann Patric
Published: November 2019

Recently, EEG recording techniques and source analysis have improved, making it feasible to tap into fast network dynamics. Yet, analyzing whole-cortex EEG signals in source space is not standard, partly because EEG suffers from volume conduction: Functional connectivity (FC) reflecting genuine functional relationships is impossible to disentangle from spurious FC introduced by volume conduction. Here, we investigate the relationship between white matter structural connectivity (SC) and large scale network structure encoded in EEG-FC. We start by confirming that FC (power envelope correlations) is predicted by SC beyond the impact of Euclidean distance, in line with the assumption that SC mediates genuine FC. We then use information from white matter structural connectivity (SC) in order to smooth the EEG signal in the space spanned by graphs derived from SC. Thereby, FC between nearby, structurally connected brain regions increases while FC between non-connected regions remains unchanged, resulting in an increase in genuine, SC-mediated FC. We analyze the induced changes in FC, assessing the resemblance between EEG- and volume-conduction-free fMRI-FC, and find that smoothing increases resemblance in terms of overall correlation and community structure. This result suggests that our method boosts genuine FC, an outcome that is of interest for many EEG network neuroscience questions.

Author summary

In this study, we combine high-density EEG recorded during resting state with white matter connectivity obtained from diffusion MRI and fiber tracking. We leverage the additional information contained in the structural connectome towards augmenting the source level EEG functional connectivity. In particular, it is known - and confirmed in this study - that the activity of brain regions that possess a direct anatomical connection is, on average, more strongly correlated than that of regions that have no such direct link. We use the structural connectome to define a graph and smooth the source reconstructed EEG signal in the space spanned by this graph. We compare the resulting “filtered” signal correlation matrices to those obtained from fMRI and find that such “graph filtering” improves the agreement between EEG and fMRI functional connectivity structure. This suggests that structural connectivity can be used to attenuate some of the limitations imposed by volume conduction.
Critical nodes reveal peculiar features of human essential genes and protein interactome
Authors: Celestini Alessandro , Cianfriglia Marco , Mastrostefano Enrico , Palma Alessandro , Castiglione Filippo , Tieri Paolo
Published: November 2019

Network-based ranking methods (e.g., centrality analysis) have found extensive use in systems biology and network medicine for the prediction of essential proteins, for the prioritization of drug targets candidates in the treatment of several pathologies and in biomarker discovery, and for human disease genes identification. We here studied the connectivity of the human protein-protein interaction network (i.e., the interactome) to find the nodes whose removal has the heaviest impact on the network, i.e., maximizes its fragmentation. Such nodes are known as Critical Nodes (CNs). Specifically, we implemented a Critical Node Heuristic (CNH) and compared its performance against other four heuristics based on well known centrality measures. To better understand the structure of the interactome, the CNs’ role played in the network, and the different heuristics’ capabilities to grasp biologically relevant nodes, we compared the sets of nodes identified as CNs by each heuristic with two experimentally validated sets of essential genes, i.e., the genes whose removal impact on a given organism’s ability to survive. Our results show that classical centrality measures (i.e., closeness centrality, degree) found more essential genes with respect to CNH on the current version of the human interactome, however the removal of such nodes does not have the greatest impact on interactome connectivity, while, interestingly, the genes identified by CNH show peculiar characteristics both from the topological and the biological point of view. Finally, even if a relevant fraction of essential genes is found via the classical centrality measures, the same measures seem to fail in identifying the whole set of essential genes, suggesting once again that some of them are not central in the network, that there may be biases in the current interaction data, and that different, combined graph theoretical and other techniques should be applied for their discovery.
A Diploid Assembly-based Benchmark for Variants in the Major Histocompatibility Complex
Authors: Chin Chen-Shan , Wagner Justin , Zeng Qiandong , Garrison Erik , Garg Shilpa , Fungtammasan Arkarachai , Rautiainen Mikko , Marschall Tobias , Dilthey Alexander T , Zook Justin M.
Published: November 2019

We develop the first human benchmark derived from a diploid assembly for the openly-consented Genome in a Bottle/Personal Genome Project Ashkenazi son (HG002). As a proof-of-principle, we focus on a medically important, highly variable, 5 million base-pair region - the Major Histocompatibility Complex (MHC). Most human genomes are characterized by aligning individual reads to the reference genome, but accurate long reads and linked reads now enable us to construct base-level accurate, phased de novo assemblies from the reads. We assemble a single haplotig (haplotype-specific contig) for each haplotype, and align reads back to each assembled haplotig to identify two regions of lower confidence. We align the haplotigs to the reference, call phased small and structural variants, and define the first small variant benchmark for the MHC, covering 21496 small variants in 4.58 million base-pairs (92 % of the MHC). The assembly-based benchmark is 99.95 % concordant with a draft mapping-based benchmark from the same long and linked reads within both benchmark regions, but covers 50 % more variants outside the mapping-based benchmark regions. The haplotigs and variant calls are completely concordant with phased clinical HLA types for HG002. This benchmark reliably identifies false positives and false negatives from mapping-based callsets, and enables performance assessment in regions with much denser, complex variation than regions covered by previous benchmarks. These methods demonstrate a path towards future diploid assembly-based benchmarks for other complex regions of the genome.
On the impact of contaminants on the accuracy of genome skimming and the effectiveness of exclusion read filters
Authors: Rachtman Eleonora , Balaban Metin , Bafna Vineet , Mirarab Siavash
Published: November 2019

The ability to detect the identity of a sample obtained from its environment is a cornerstone of molecular ecological research. Thanks to the falling price of shotgun sequencing, genome skimming, the acquisition of short reads spread across the genome at low coverage, is emerging as an alternative to traditional barcoding. By obtaining far more data across the whole genome, skimming has the promise to increase the precision of sample identification beyond traditional barcoding while keeping the costs manageable. While methods for assembly-free sample identification based on genome skims are now available, little is known about how these methods react to the presence of DNA from organisms other than the target species. In this paper, we show that the accuracy of distances computed between a pair of genome skims based on k-mer similarity can degrade dramatically if the skims include contaminant reads; i.e., any reads originating from other organisms. We establish a theoretical model of the impact of contamination. We then suggest and evaluate a solution to the contamination problem: Query reads in a genome skim against an extensive database of possible contaminants (e.g., all microbial organisms) and filter out any read that matches. We evaluate the effectiveness of this strategy when implemented using Kraken-II, in detailed analyses. Our results show substantial improvements in accuracy as a result of filtering but also point to limitations, including a need for relatively close matches in the contaminant database.
The adaptive potential of the middle domain of yeast Hsp90
Authors: Cote-Hammarlof Pamela A. , Fragata Inês , Flynn Julia , Mavor David , Zeldovich Konstantin B. , Bank Claudia , Bolon Daniel N.A.
Published: November 2019

The distribution of fitness effects (DFE) of new mutations across different environments quantifies the potential for adaptation in a given environment and its cost in others. So far, results regarding the cost of adaptation across environments have been mixed, and most studies have sampled random mutations across different genes. Here, we quantify systematically how costs of adaptation vary along a large stretch of protein sequence by studying the DFEs of the same ≈2300 amino-acid changing mutations obtained from deep mutational scanning of 119 amino acids in the middle domain of the heat-shock protein Hsp90 in five environments. This region is known to be important for client binding, stabilization of the Hsp90 dimer, stabilization of the N-terminal-Middle and Middle-C-terminal interdomains, and regulation of ATPase-chaperone activity. Interestingly, we find that fitness correlates well across diverse stressful environments, with the exception of one environment, diamide. Consistent with this result, we find little cost of adaptation; on average only one in seven beneficial mutations is deleterious in another environment. We identify a hotspot of beneficial mutations in a region of the protein that is located within an allosteric center. The identified protein regions that are enriched in beneficial, deleterious, and costly mutations coincide with residues that are involved in the stabilization of Hsp90 interdomains and stabilization of client binding interfaces, or residues that are involved in ATPase chaperone activity of Hsp90. Thus, our study yields information regarding the role and adaptive potential of a protein sequence that complements and extends known structural information.
Simple and low-cost amplifier system for the study of a ventral nerve action potential in earthworm
Authors: Jorquera Orlando
Published: November 2019

Basic Biophysics or Neurobiology courses encounter problems when starting their practices due to the complexity and high cost of the equipment. As a consequence, these experiences are replaced by simulation software, leading students to boredom and disinterest, and finally to the lack of understanding of the basic principles of the phenomenon observed. Classical nerve conduction studies for the visualization of action potentials are an example of this, being able to be developed with simple and low-cost amplification circuits, as described in this article. The system showed stability, expected amplification and high signal-to-noise ratio. The action potential of the medial giant fiber (MGF) as lateral giant fiber (LGF) in the ventral nerve cord of the earthwormsLumbricus terrestriswas recorded. The experimental system has met expectations and regains practical, effective and stimulating learning for students.
Gain-of-function genetic screen of the kinome reveals BRSK2 as an inhibitor of the NRF2 transcription factor
Authors: Tamir Tigist Y , Bowman Brittany M , Agajanian Megan J , Goldfarb Dennis , Schrank Travis P , Stohrer Trent , Hale Andrew E , Siesser Priscila F , Weir Seth J , Murphy Ryan M , LaPak Kyle M , Weissman Bernard E , Moorman Nathaniel J , Ben Major M.
Published: November 2019

NFE2L2/NRF2 is a transcription factor and master regulator of cellular antioxidant response. Aberrantly high NRF2-dependent transcription is recurrent in human cancer, and conversely NRF2 protein levels as well as activity is diminished with age and in neurodegenerative disorders. Though NRF2 activating drugs are clinically beneficial, NRF2 inhibitors do not yet exist. Here we used a gain-of-function genetic screen of the kinome to identify new druggable regulators of NRF2 signaling. We found that the understudied protein kinase Brain Specific Kinase 2 (BRSK2) and the related BRSK1 kinases suppress NRF2-dependent transcription and NRF2 protein levels in an activity-dependent manner. Integrated phosphoproteomics and RNAseq studies revealed that BRSK2 drives AMPK activation and suppresses mTOR signaling. As a result, BRSK2 kinase activation suppressed ribosome-RNA complexes, global protein synthesis, and NRF2 protein levels. Collectively, our data establish the catalytically active BRSK2 kinase as a negative regulator of NRF2 via the AMPK/mTOR signaling. This signaling axis may prove useful for therapeutically targeting NRF2 in human diseases.

Summary Statement

BRSK2 suppresses NRF2 signaling by inhibiting protein synthesis through mTOR downregulation.
The expression of YAP1 is increased in high-grade prostatic adenocarcinoma but is reduced in neuroendocrine prostate cancer
Authors: Cheng Siyuan , Prieto-Dominguez Nestor , Yang Shu , Connelly Zachary M. , StPierre Samantha , Rushing Bryce , Watkins Andy , Shi Lawrence , Lakey Meredith , Baiamonte Lyndsey Buckner , Fazili Tajammul , Lurie Aubrey , Corey Eva , Shi Runhua , Yeh Yunshin , Yu Xiuping
Published: November 2019

BACKGROUND

After long-term androgen deprivation therapy, 25-30% prostate cancer (PCa) acquires an aggressive neuroendocrine (NE) phenotype. Dysregulation of YAP1, a key transcription coactivator of the Hippo pathway, has been related to cancer progression. However, its role in neuroendocrine prostate cancer (NEPC) has not been assessed.

METHODS

Immunohistochemistry was used to evaluate YAP1 protein levels during PCa initiation and progression. YAP1 knockdown and luciferase reporter assays were used to evaluate the ability of YAP1 to modulate Wnt/beta-Catenin signaling.

RESULTS

YAP1 expression was present in the basal epithelial cells in benign prostatic tissues, lost in low grade PCa, but elevated in high grade prostate adenocarcinomas. Interestingly, the expression of YAP1 was reduced/lost in both human and mouse NEPC. Finally, YAP1 knockdown in PCa cells activates Wnt/beta-Catenin signaling, which has been implicated in NE differentiation of PCa, supporting a functional involvement of the loss of YAP1 expression in NEPC development.

CONCLUSIONS

The expression of YAP1 is elevated in high grade prostate adenocarcinomas while lost in NEPC. Reduced YAP1 activates Wnt/beta-Catenin signaling in PCa cells. These results suggest that when applied to PCa patients, YAP1 inhibitors shall be used with caution.
Genomic Background Governs Opposing Responses to Nalidixic Acid Upon Megaplasmid Acquisition inPseudomonas
Authors: Baltrus David A. , Smith Caitlin , Derrick MacKenzie , Leligdon Courtney , Rosenthal Zoe , Mollico Madison , Moore Andrew , Clark Meara
Published: November 2019

Horizontal gene transfer is a significant driver of evolutionary dynamics across microbial populations. Although the benefits of the acquisition of new genetic material are often quite clear, experiments across systems have demonstrated that gene transfer events can cause significant phenotypic changes and entail fitness costs in a way that is dependent on the genomic and environmental context. Here we test for the generality of one previously identified cost, sensitization of cells to the antibiotic nalidixic acid after acquisition of a ∼1Mb megaplasmid, across Pseudomonas strains and species. Overall, we find that the presence of this megaplasmid sensitizes many different Pseudomonas strains to nalidixic acid, but that this same horizontal gene transfer event increases resistance ofPseudomonas putidaKT2440 to nalidixic acid across assays as well as to ciprofloxacin under competitive conditions. These phenotypic results are not easily explained away as secondary consequences of overall fitness effects and appear to occur independently of another cost associated with this megaplasmid, sensitization to higher temperatures. Lastly, we draw parallels between these reported results and the phenomenon of sign epistasis forde novomutations and explore how context dependence of effects of plasmid acquisition could impact overall evolutionary dynamics and the evolution of antimicrobial resistance.

Importance

Numerous studies have demonstrated that gene transfer events (e.g. plasmid acquisition) can entail a variety of costs that arise as byproducts of the incorporation of foreign DNA into established physiological and genetic systems. These costs can be ameliorated through evolutionary time by the occurrence of compensatory mutations, which stabilize presence of a horizontally transferred region within the genome but which also may skew future adaptive possibilities for these lineages. Here we demonstrate another possible outcome, that phenotypic changes arising as a consequence of the same horizontal gene transfer event are costly to some strains but may actually be beneficial in other genomic backgrounds under the right conditions. These results provide new a new viewpoint for considering conditions that promote plasmid maintenance and highlight the influence of genomic and environmental contexts when considering amelioration of fitness costs after HGT events.
Pseudohyphal growth of the emerging pathogenCandida aurisis triggered by genotoxic stress through the S phase checkpoint
Authors: Bravo Ruiz Gustavo , Ross Zoe K. , Gow Neil A.R. , Lorenz Alexander
Published: November 2019

The morphogenetic switching between yeast cells and filaments (true hyphae and pseudohyphae) is a key cellular feature required for full virulence in many polymorphic fungal pathogens, such asCandida albicans. In the recently emerged yeast pathogenCandida auris, occasional elongation of cells has been reported. However, environmental conditions and genetic triggers for filament formation have remained elusive. Here, we report that induction of DNA damage and perturbation of replication forks by treatment with genotoxins, such as hydroxyurea, methyl methanesulfonate, and the clinically relevant fungistatic 5-fluorocytosine, causes filamentation inC. auris. The filaments formed were characteristic of pseudohyphae and not parallel-sided true hyphae. Pseudohyphal growth is apparently signalled through the S phase checkpoint and, interestingly, is Tup1-independent inC. auris. Intriguingly, the morphogenetic switching capability is strain-specific inC. auris, highlighting the heterogenous nature of the species as a whole.

IMPORTANCE

Candida aurisis a newly emerged fungal pathogen of humans. This species was first reported in 2009, when it was identified in an ear infection of a patient in Japan. However, despite intense interest in this organism as an often multidrug-resistant fungus there is little knowledge about its cellular biology. During infection of human patients, fungi are able to change cell shape from ellipsoidal yeast cells to elongated filaments to adapt to various conditions within the host organism. There are different types of filaments, which are triggered by reactions to different cues.Candida aurisfails to form filaments when exposed to triggers that stimulate yeast-filament morphogenesis in other fungi. Here, we show that it does form filaments when its DNA is damaged. These conditions might arise whenCandida auriscells interact with host immune cells, or growing in certain host tissues (kidney, bladder), or during treatment with antifungal drugs.
Squamous trans-differentiation of pancreatic cancer cells promotes stromal inflammation
Authors: Somerville Tim D.D. , Biffi Giulia , Daßler-Plenker Juliane , Miyabayashi Koji , Xu Yali , Maia-Silva Diogo , Klingbeil Olaf , Demerdash Osama E. , Egeblad Mikala , Tuveson David A. , Vakoc Christopher R.
Published: November 2019

A highly aggressive subset of pancreatic ductal adenocarcinomas undergo trans-differentiation into the squamous lineage during disease progression. While the tumorigenic consequences of this aberrant cell fate transition are poorly understood, recent studies have identified a role for the master regulator TP63 in this process. Here, we investigated whether squamous trans-differentiation of pancreatic cancer cells can influence the phenotype of non-neoplastic cells in the tumor microenvironment. Conditioned media experiments revealed that squamous-subtype pancreatic cancer cells secrete factors that convert quiescent pancreatic stellate cells into a specialized subtype of cancer-associated fibroblasts (CAFs) that express inflammatory genes at high levels. We use gain- and loss-of-function approachesin vivoto show that squamous-subtype pancreatic tumor models become enriched with inflammatory CAFs and neutrophils in a TP63-dependent manner. These non cell-autonomous effects occur, at least in part, through TP63-mediated activation of enhancers at pro-inflammatory cytokine loci, which includesIL1Aas a key target. Taken together, our findings reveal enhanced tissue inflammation as a consequence of squamous trans-differentiation in pancreatic cancer, thus highlighting an instructive role of tumor cell lineage in reprogramming the stromal microenvironment.
Systems genetics of the Drosophila metabolome
Authors: Zhou Shanshan , Morgante Fabio , Geisz Matthew S. , Ma Junwu , Anholt Robert R.H. , Mackay Trudy F.C.
Published: November 2019

How effects of DNA sequence variants are transmitted through intermediate endophenotypes to modulate organismal traits remains a central question in quantitative genetics. This problem can be addressed through a systems approach in a population in which genetic polymorphisms, gene expression traits, metabolites, and complex phenotypes can be evaluated on the same genotypes. Here, we focused on the metabolome, which represents the most proximal link between genetic variation and organismal phenotype, and quantified metabolite levels in 40 lines of the Drosophila melanogaster Genetic Reference Panel. We identified sex-specific modules of genetically correlated metabolites and constructed networks that integrate DNA sequence variation and variation in gene expression with variation in metabolites and organismal traits, including starvation stress resistance and male aggression. Finally, we asked to what extent SNPs and metabolites can predict trait phenotypes and generated trait- and sex-specific prediction models that provide novel insights about the metabolomic underpinnings of complex phenotypes.
Agomelatine–hydroquinone (1:1) cocrystal: novel polymorphs and their thermodynamic relationship
Authors: Lee Min-Jeong , Aitipamula Srinivasulu , Choi Guang J. , Chow Pui Shan
Published: November 2019

Polymorphism of active pharmaceutical ingredients (APIs) is of significance in the pharmaceutical industry because it can affect the quality, efficacy and safety of the final drug product. In this regard, polymorphic behavior of cocrystals is no exception because it can influence the development of cocrystals as potential drug formulations. The current contribution aims to introduce two novel polymorphs [forms (III) and (IV)] of agomelatine–hydroquinone (AGO-HYQ) cocrystal and to describe the thermodynamic relationship between the cocrystal polymorphs. All polymorphs were characterized using powder X-ray diffraction, differential scanning calorimetry, hot-stage microscopy and solubility measurements. In addition, the crystal structure of form (II), which has been previously solved from powder diffraction data [Prohens et al. (2016), Cryst. Growth Des.
16, 1063–1070] and form (III) were determined from the single-crystal X-ray diffraction data. Thermal analysis revealed that AGO-HYQ cocrystal form (III) exhibits a higher melting point and a lower heat of fusion than those of form (II). According to the heat of fusion rule, the polymorphs are enantiotropically related, with form (III) being stable at higher temperatures. Our results also show that the novel form (IV) is the most stable form at ambient conditions and it transforms into form (II) on heating, and therefore, the two polymorphs are enantiotropically related. Furthermore, solubility and van't Hoff plot results suggest that the transition points are approximately 339 K for the pair form (IV)–(II) and 352 K for the pair form (II)–(III).
Empirical analysis of doctoral candidates’ innovative personality model based on grey target decision making
Authors: Sun Caiyun
Published: November 2019

Purpose

The purpose of this paper is to analyze the reliability and validity of doctoral candidates’ innovative personality model.

Design/methodology/approach

Based on doctoral candidates’ innovative personality model, this study took the best correlation and the worst correlation into account to predict and demonstrate their innovative ability tendencies. Matlab R2016a, a program of software programming, was used to calculate the contribution degree of each personality factor of doctoral candidates to their innovative ability tendencies.

Findings

The reliability and validity of doctoral candidates’ innovative personality model based on grey target theory have been verified, and the prediction for doctoral candidates’ innovative ability tendencies can be realized on the basis of this model.

Practical implications

Scientific and reasonable doctoral candidates’ innovative personality model can play a good guiding role, and its research results have certain practical significance for selecting innovative doctoral candidates, ensuring the training quality of doctoral candidates and cultivating the innovative ability of doctoral candidates. It can be promoted and applied on the basis of its trial operation in Jiangsu.

Originality/value

With regard to the relative degree of the influence of doctoral candidates’ individual personality factors, previous researchers seldom carried out the quantitative research. In this paper, the author sought a quantitative method to describe the degree of such influence and constructed the doctoral candidates’ innovative personality model based on grey target decision making. This study took the positive and negative off-target distance into account and demonstrated the rationality and validity of doctoral candidates’ innovative personality model.
The hidden historiography of migration and Australian schooling
Authors: Proctor Helen
Published: November 2019

Purpose

Despite Australia’s history as an exemplary migrant nation, there are gaps in the literature and a lack of explicit conceptualisation of either “migrants” or “migration” in the Australian historiography of schooling. The purpose of this paper is to seek out traces of migration history that nevertheless exist in the historiography, despite the apparent silences.

Design/methodology/approach

Two foundational yet semi-forgotten twentieth-century historical monographs are re-interpreted to support a rethinking of the relationship between migration and settler colonialism in the history and historiography of Australian schooling.

Findings

These texts, from their different school system (state/Catholic) orientations, are, it is argued, replete with accounts of migration despite their apparent gaps, if read closely. Within them, nineteenth-century British migrants are represented as essentially entitled constituents of the protonation. This is a very different framing from twentieth century histories of migrants as minority or “other”.

Originality/value

Instead of an academic reading practice that dismisses and simply supersedes old work, this paper proposes that fresh engagements with texts from the past can yield new insights into the connections between migration, schooling and colonialism. It argues that the historiography of Australian schooling should not simply be expanded to include or encompass the stories of “migrants” within a “minority studies” framework, although there is plenty of useful work yet to be accomplished in that area, but should be re-examined as having been about migration all along.
The impact of training and development practices on innovation and financial performance
Authors: Manresa Alba , Bikfalvi Andrea , Simon Alexandra
Published: November 2019

Purpose

Over recent years, firms have been implementing novel human resource practices. The purpose of this paper is to analyse four specific training practices to determine if and up to what extent the adoption of such practices affects innovation and financial performance.

Design/methodology/approach

A Spanish sub-sample of the European Manufacturing Survey is used to contain the responses of 162 manufacturing firms.

Findings

The positive relation between T&D practices and innovative performance was partially accepted, as new-to-the-firm products and new services had a significant relation with these practices. Conversely, the hypothesis stating that there is a positive relation between a new-to-the-market product and the aforementioned T&D practices was rejected. Furthermore, the positive relation between these and financial performance was partially accepted.

Research limitations/implications

This research presents the following limitation: the small number of responses restricts the general reliability of the findings. The inclusion of other countries’ data using the same questionnaire would further enrich the analysis.

Practical implications

First, general training and development is not enough; thus, the present study evidences the positive results of specific training practices such as training and development for creativity and innovation (TD4CI) on firm performances. Second, it also reveals a relation between training practices and innovation by differentiating among the three dimensions of innovation (new product to the firm, new product to the market and new services). Moreover, the present research highlights the benefits of implementing these types of practices, not only for innovation performance but also for financial performance. This paper also suggests that not all the training practices have the same impact on firm performance. Consequently, the company should be clear about their main aim to obtain the highest performance. The third contribution is based on the Spanish context wherein training is not considered as an important organisational function. Thus, this study provides positive results showing that TD4CI might enhance firm performance. Last, the degree of detail of the different training practices analysed, the recent nature of the data related to their implementation and the link between implementation and organisation performance are also part of the contribution of the present analyses.

Originality/value

This research offers recent and relevant data about implementing novel T&D practices and their relation with firm performance.
Tribological performance of a surface textured meso scale air bearing
Authors: Hingawe Nilesh D. , Bhore Skylab P.
Published: November 2019

Purpose

The purpose of this study is to improve the tribological performance of meso scale air journal bearing by adopting texture on the bearing surface.

Design/methodology/approach

The present study is based on numerical analysis. The detailed numerical investigation is carried out using a fluid flow based thin-film model in COMSOL 5.2 software.

Findings

The influence of texture design parameters: geometry (shape, orientation and slender ratio), and position on the tribological performance of meso scale air journal bearing is investigated. It is found that texture shape has a strong influence on the tribological characteristics such as load capacity and friction coefficient of the bearing. Slender texture improves the load capacity, but it has a negligible effect on the reduction of friction coefficient. In contrast, texture orientation is found to be insignificant for both increasing load capacity and decreasing friction coefficient. Furthermore, the maximum improvement in load capacity is obtained for partially textured bearing, but the minimum friction coefficient is achieved for full texturing.

Originality/value

The present study investigates the influence of texture design parameters viz geometry (shape, orientation and slender ratio), and position on the tribological performance of meso scale air journal bearing.
International buyers’ repurchase intentions in a Chinese cross-border e-commerce platform
Authors: Mou Jian , Cohen Jason , Dou Yongxiang , Zhang Bo
Published: November 2019

Purpose

The purpose of this paper is to develop and test a model of the uncertainties and benefits influencing the repurchase intentions of buyers in cross-border e-commerce (CBEC).

Design/methodology/approach

The authors draw on the valence framework to hypothesize effects of positive valences (utilitarian benefits) along with negative valences (pre- and post-contractual uncertainties) on buyers’ repeat purchase intentions. Data were collected using an online survey from 378 international B2C buyers on a CBEC platform in China.

Findings

Results explain 51.4 percent of the variance and reveal that overall value, as determined by monetary saving, convenience and product offerings as positive valences, exerts the strongest effect on repeat purchase intention. However, negative valences remain significant, and are particularly salient for female shoppers.

Research limitations/implications

The authors extend the valence theory into the study of repeat purchase behavior and contribute to much needed literature on why consumers return to repurchase from a CBEC platform.

Practical implications

Repeat purchase and loyalty of online consumers is essential for success of e-commerce providers. The results help online providers competing in international markets understand how buyers form repurchase intentions based on their evaluations of both value and uncertainty.

Originality/value

Buyer behavior in CBEC has received relatively less attention than domestic e-commerce. This paper is among the first to examine how both positive and negative valences combine to effect repurchase intention of international buyers in CBEC.
Sustainable practices in SMEs: reducing the ecological footprint
Authors: Franco Mário , Rodrigues Margarida
Published: November 2019

Purpose

The purpose of this study to focus on sustainable entrepreneurship practices in small and medium-sized enterprises (SMEs), thus aiming to understand the reasons owners-managers implement them as well as the benefits they provide after considering the three domains of sustainable development: environmental, social and economic.

Design/methodology/approach

A qualitative approach was adopted using two Portuguese cases (SME). Data were obtained from interviews and documentary analysis.

Findings

From content analysis of the interviews held, the results obtained show that both SMEs studied are concerned about sustainable practices and development. They have competences directing them towards a sustainable entrepreneurship.

Practical implications

The study contributes to understanding the benefits of adopting sustainable entrepreneurial practices in the SME context and helping these firms’ managers reformulate more appropriate and effective strategies and actions to ground these firms in a process of continuous improvement, especially in reducing their environmental footprint.

Originality/value

Although SMEs are numerous and central in the dynamics of the world economy, sustainable entrepreneurial practices have not been studied as a vehicle to reduce the ecological footprint. This holds particularly true for the realm of SMEs.
Exchange rate exposure and firm productivity in India
Authors: Mohapatra Sonali Madhusmita
Published: November 2019

Purpose

The purpose of this paper is to investigate the linkage between exchange rate exposure and firms’ productivity in India. This study also tries to compare the effects of exchange rate exposure on the productivity of the pre- and post-financial crisis periods and also between export- and import-oriented firms.

Design/methodology/approach

By using the annual data of 232 manufacturing and service sector firms for the period of 2000-2013, this paper examines the exchange rate exposure and firms’ performance in India. In the first stage, the two-factor regression model, Adler and Dumas, is used, and in the second stage, the Levinsohn and Petrin (2003) approach is used for estimating the total factor productivity of significant firms. Finally, for examining the relationship between exchange rate exposure and productivity, the instrumental variable panel data regression model is used.

Findings

This study observes that a negative relation exists between the appreciation of exchange rate exposure and firms’ productivity. The study also reveals that the export-oriented firms make loss during exchange rate appreciation which decreases the productivity. The financial crisis has the negative impact on productivity, as well.

Originality/value

Although there are an ample number of studies which examined the effects of the exchange rate on firm’s export, growth, investment, however impact of exchange rate exposure on productivity at firm level is scanty. This study tries not only to compare the effects of exchange rate exposure on the productivity of the pre- and post-financial crisis periods but also between the export- and import-oriented firms which is another innovation of this study.
The effect of changing fiscal year-ends on audit fees and audit quality
Authors: Pacheco Paredes Angel Arturo , Wheatley Clark
Published: November 2019

Purpose

This study aims to extend recent research analyzing the effect of auditor busyness on audit quality. Specifically, this study explores the effect on audit quality of a change of fiscal year-end to or from an audit firm’s busy period.

Design/methodology/approach

Empirical archival.

Findings

When firms change their fiscal year-end to a period when the auditor is less busy, client firms are rewarded with lower audit fees and auditors are rewarded with a reduction in required effort. This study finds no difference in the level of audit quality after a change in fiscal year-end.

Practical implications

There are significant implications for audit firms as they may gain cost advantages by successfully promoting off-season fiscal year-ends, and reduce the negative effect on employees associated with “busy season” stress. Similarly, client firms may find that audit costs are reduced when they adopt a less “busy” fiscal year-end.

Social implications

These results have policy implications for regulators because regulators often dictate the fiscal year-end for certain industries or traded securities. Such dictates may thus introduce inefficiencies into the market for audit services.

Originality/value

These results should guide regulators in their decisions to dictate fiscal year-ends and firms in their choice of reporting periods.