bluuebunny/crossref_metadata_2025 huggingface dataset:
Generalization as diffusion: human function learning on graphs
Authors: Wu Charley M. , Schulz Eric , Gershman Samuel J.
Published: February 2019

From social networks to public transportation, graph structures are a ubiquitous feature of life. Yet little is known about how humans learn functions on graphs, where relationships are defined by the connectivity structure. We adapt a Bayesian framework for function learning to graph structures, and propose that people perform generalization by diffusing observed function values across the graph. We test the predictions of this model by asking participants to make predictions about passenger volume in a virtual subway network. The model captures both generalization and confidence judgments, and is a quantitatively superior account relative to several heuristic models. Our work suggests that people exploit graph structure to make generalizations about functions in complex discrete spaces.
Modeling of fibrotic lung disease using 3D organoids derived from human pluripotent stem cells
Authors: Snoeck Hans-Willem , Strikoudis Alexandros , Loffredo Lucas , Chen Ya-Wen
Published: February 2019

Idiopathic pulmonary fibrosis (IPF) is an intractable interstitial lung disease for which no curative treatment is available except for lung transplantation. Its pathogenesis is unclear, but a role for injury to type 2 alveolar epithelial cells is hypothesized. Recessive mutations in some, but not all genes implicated in Hermansky-Pudlak Syndrome (HPS) cause HPS-associated interstitial pneumonia (HPSIP), a clinical entity similar to IPF. We previously reported that mutation in HPS1 in embryonic stem cells-derived 3D lung organoids caused fibrotic changes. Here we show that introduction of all HPS mutations associated with HPSIP (HPS1, 2 and 4) promote fibrosis in lung organoids, while mutation in HSP8, which is not associated with HPSIP, does not. Furthermore, genome-expression analysis of epithelial cells derived from these organoids revealed significant overlap with similar analyses of both affected and unaffected lung tissue of non-HPS IPF patients. Importantly, this analysis showed upregulation of interleukin-11 in HPS-mutant fibrotic organoids and in fibrotic and unaffected lung tissue from IPF patients. Furthermore, IL-11 induced fibrosis in WT organoids, while its deletion prevented fibrosis in fibrotic HPS4-mutant organoids, suggesting IL-11 as a therapeutic target in IPF and HPSIP. hPSC-derived 3D lung organoids are therefore a valuable resource to model fibrotic lung disease.
Genome-wide expression analysis identifies core components during iron starvation in hexaploid wheat
Authors: Kaur Gazaldeep , Shukla Vishnu , Kumar Anil , Kaur Mandeep , Goel Parul , Singh Palvinder , Shukla Anuj , Kaur Jaspreet , Singh Jagtar , Mantri Shrikant , Rouached Hatem , Pandey Ajay Kumar
Published: February 2019

Iron is one of essential micronutrient for all organisms. Its deficiency causes a severe loss in crops yield. Nevertheless, our current understanding on major crops response to Fe deficiency remains limited. Herein, we investigated the effect of Fe deprivation at both transcriptomic and metabolic levels in hexaploid wheat. A genome-wide gene expression reprogramming was observed with a total of 5854 genes showing differential expression in roots of wheat subjected to Fe-starved medium. Subsequent, analysis revealed a predominance of strategy-II mode of Fe uptake, with induced genome bias contribution from the A and B genomes. In general, the predominance of genes encoding for nicotianamine synthase, yellow stripe like transporters, metal transporters, ABC transporters and zinc-induced facilitator-like protein was noticed. Our transcriptomic data were in agreement with the GC-MS analysis that showed an enhancement of accumulation of various metabolites such as fumarate, malonate, succinate and xylofuranose, which could be linked for enhancing Fe-mobilization. Interestingly, Fe starvation causes a significant temporal increase of glutathione-S-transferase both at transcriptional and enzymatic activity, which indicate the important role of glutathione in the response to Fe starvation in wheat roots. Taken together, our result provides new insight on wheat response to Fe starvation and lays foundation to design strategies to improve Fe nutrition in crops.
Unlocking a signal of introgression from codons in Lachancea kluyveri using a mutation-selection model
Authors: Landerer Cedric , O’Meara Brian C. , Zaretzki Russell , Gilchrist Michael A.
Published: February 2019

For decades, codon usage has been used as a measure of adaptation for translational efficiency and translation accuracy of a gene’s coding sequence. These patterns of codon usage reflect both the selective and mutational environment in which the coding sequences evolved. Over this same period, gene transfer between lineages has become widely recognized as an important biological phenomenon. Nevertheless, most studies of codon usage implicitly assume that all genes within a genome evolved under the same selective and mutational environment, an assumption violated when introgression occurs. In order to better understand the effects of introgression on codon usage patterns and vice versa, we examine the patterns of codon usage in Lachancea kluyveri, a yeast which has experienced a large introgression. We quantify the effects of mutation bias and selection for translation efficiency on the codon usage pattern of the endogenous and introgressed exogenous genes using a Bayesian mixture model, ROC SEMPPR, which is built on mechanistic assumptions about protein synthesis and grounded in population genetics.

We find substantial differences in codon usage between the endogenous and exogenous genes, and show that these differences can be largely attributed to differences in mutation bias favoring A/T ending codons in the endogenous genes while favoring C/G ending codons in the exogenous genes. Recognizing the two different signatures of mutation bias and selection improves our ability to predict protein synthesis rate by 42% and allowed us to accurately assess the decaying signal of endogenous codon mutation and preferences. In addition, using our estimates of mutation bias and selection, we identify Eremothecium gossypii as the closest relative to the exogenous genes, providing an alternative hypothesis about the origin of the exogenous genes, estimate that the introgression occurred ∼ 6 × 108 generation ago, and estimate its historic and current selection against mismatched codon usage.

Our work illustrates how mechanistic, population genetic models like ROC SEMPPR can separate the effects of mutation and selection on codon usage and provide quantitative estimates from sequence data.
Quantifying bacterial fitness in intracellular dynamics
Authors: Paupério Francisco F. S. , Gjini Erida
Published: February 2019

Understanding bacterial infection is challenging because it involves a complex interplay of host, pathogen, and intervention factors. To design successful control measures, mathematical models that quantify such interplay at the level of populations and phenotypes are needed. Here, we study a key aspect of intracellular infection: the interaction dynamics between bacteria and target cells, applicable to pathogens such as Salmonella, E. coli or Listeria monocytogenes. Our mathematical model focuses on the macrophage-bacteria system, implicitly accounting for host immunity, and illustrates three infection scenarios driven by the balance between bacterial growth and death processes. Our analysis reveals critical parameter combinations for the intracellular vs. extracellular fitness advantage of persistent bacteria, and the drivers of overall infection success across acute and persistent regimes. Our results provide quantitative insights on transitions from persistent, to acute, to containment of infection, and suggest biological parameters, such as infected macrophage apoptosis rate and burst size, as suitable intervention targets.
Enhancer locus in ch14q23.1 modulates brain asymmetric temporal regions involved in language processing
Authors: Le Guen Yann , Leroy François , Philippe Cathy ,   IMAGEN consortium, Mangin Jean-François , Dehaene-Lambertz Ghislaine , Frouin Vincent
Published: February 2019

Identifying the genes that contribute to the variability in brain regions involved in language processing may shed light on the evolution of brain structures essential to the emergence of language in Homo sapiens. The superior temporal asymmetrical pit (STAP), which is not observed in chimpanzees, represents an ideal phenotype to investigate the genetic variations that support human communication. The left STAP depth was significantly associated with a predicted enhancer annotation located in the 14q23.1 locus, between DACT1 and KIAA0586, in the UK Biobank British discovery sample (N=16,515). This association was replicated in the IMAGEN cohort (N=1,726) and the UK Biobank non-British validation sample (N=2,161). This genomic region was also associated to a lesser extent with the right STAP depth and the formation of sulcal interruptions, plis de passage, in the bilateral STAP but not with other structural brain MRI phenotypes, highlighting its notable association with the superior temporal regions. Diffusion MRI emphasized an association with the fractional anisotropy of the left auditory fibers of the corpus callosum and with networks involved in linguistic processing in resting-state functional MRI. Overall, this evidence demonstrates a specific relationship between this locus and the establishment of the superior temporal regions that support human communication.
Molecular dissection of the cellular response to mechanical stress
Authors: Zuela-Sopilniak Noam , Dorfman Jehudith , Gruenbaum Yosef
Published: February 2019

The response of cells to mechanical stress is crucial for many cellular functions, yet its molecular mechanisms are not yet fully understood. Previous studies of the cellular response to mechanical stress were performed on cultured cells or isolated muscle fibers devoid of cell and/or tissue contexts. Thus, the emerging results were limited to the specific cell types or tissues analyzed and dependent on the growth matrix elasticity. In the present study, we looked for changes in early gene expression in response to mechanical whole body stretching of livingC. elegans. Our transcriptome analysis revealed upregulation of genes involved in cuticle development, stress response and several signaling pathways such as WNT, TGFβ, AMPK and Hedgehog signaling. These findings indicate that protecting against mechanical insults entails providing additional support to the mechanically resilient protective cuticle, and that proper recovery from mechanical stretching requires an intact Hedgehog signaling pathway. Recent findings suggest an important role for the nuclear lamina in mediating cellular mechanical response. The nuclear lamina is composed mainly of lamins, which are nuclear intermediate filament-type proteins needed, among other functions to maintain nuclear integrity. One particular area of interest are laminopathies, which are caused by mutations in lamin. Stretched animals expressing the Emery Dreifuss Muscular Dystrophy (EDMD) linked L535P lamin mutation, showed further upregulation of cytoskeleton organization, cellular respiration and mitochondrial protein-unfolding stress response genes, most likely to compensate for aberrant muscle tissue function. These findings provide a broad multi-dimensional picture of thein vivogenetic response of live animals to mechanical stress, highlighting previously unreported mechano-sensitive genes and molecular pathways.
Identification of novel mobilized colistin resistance gene mcr-9 in a multidrug-resistant, colistin-susceptible Salmonella enterica serotype Typhimurium isolate using a combination of high-throughput, in silico screening and functional analysis
Authors: Carroll Laura M , Gaballa Ahmed , Guldimann Claudia , Sullivan Genevieve , Henderson Lory O , Wiedmann Martin
Published: February 2019

Mobilized colistin resistance (mcr) genes are plasmid-borne genes that confer resistance to colistin, an antibiotic used to treat severe bacterial infections. To date, eight known mcr homologues have been described (mcr-1 to -8). Here, we describe mcr-9, a novel mcr homologue, detected in a Salmonella enterica serotype Typhimurium (S. Typhimurium) genome using an in silico approach, followed by experimental functional analysis. The amino acid sequence of mcr-9, detected in a multidrug resistant (MDR) S. Typhimurium strain isolated from a human patient in Washington State in 2010, most closely resembled mcr-3, aligning with 64.5% amino acid identity and 99.5% coverage using translated nucleotide blast. The S. Typhimurium strain was tested for phenotypic resistance to colistin and was found to be sensitive at the 2 mg/L European Committee on Antimicrobial Susceptibility Testing breakpoint under the tested conditions. To determine whether it was capable of conferring resistance to colistin when expressed in a heterologous host, mcr-9 was cloned in colistin-susceptible Escherichia coli NEB5α under an IPTG-induced promoter. Expression of mcr-9 conferred resistance to colistin in E. coli NEB5α at 1, 2, and 2.5 mg/L colistin, albeit at a lower level when compared to mcr-3. Pairwise comparisons of the predicted protein structures associated with all nine mcr homologues (Mcr-1 to -9) revealed that Mcr-9, Mcr-3, and Mcr-7 share a high degree of similarity at the structural level. The results of our approach indicate that mcr-9 is capable of conferring phenotypic resistance to colistin in Enterobacteriaceae and should be immediately considered when monitoring plasmid-mediated colistin resistance. Importance: Colistin is a last-resort antibiotic that is used to treat severe infections caused by MDR and extensively drug resistant (XDR) bacteria. The World Health Organization (WHO) has designated colistin as a Highest Priority Critically Important Antimicrobial for human medicine (WHO, Critically Important Antimicrobials for Human Medicine, 5th Revision, 2017), as it is often one of the only therapies available for treating serious bacterial infections in critically ill patients. Plasmid-borne mcr genes that confer resistance to colistin pose a threat to public health at an international scale, as they can be transmitted via horizontal gene transfer and have the potential to spread globally. Therefore, the establishment of a complete reference of mcr genes that can be used to screen for plasmid-mediated colistin resistance is essential for developing effective control strategies.
Semantic coding in the occipital cortex of early blind individuals
Authors: Abboud Sami , Engemann Denis A. , Cohen Laurent
Published: February 2019

The visual cortex of early blind individuals is reorganized to support cognitive functions distinct from vision. Research suggests that one such prominent function is language. However, it is unknown whether the visual cortex of blind individuals codes for word meaning. We addressed this question by comparing neuronal activity evoked by a semantic decision task, using magnetoencephalography (MEG), between 12 early blind and 14 sighted participants otherwise comparable with regard to gender, age and education. We found that average brain responses to thousands of auditory word stimuli followed similar time courses in blind and sighted participants. However, in blind participants only, we found a sustained enhancement of activity in the visual cortex. Moreover, across the whole brain, we found an effect of semantic category from about 400 ms after word onset. Strikingly, in blind participants, semantic categories were discriminable starting 580 ms after word onset from signal captured by sensors sensitive to the visual cortex. We replicated the analyses in time windows locked to stimulus onset and behavioral response, using both classical hypothesis testing and machine learning for single-trial classification. Semantic decisions were well classified in all participants (AUC ∼ 0.60), but generalization capacity across participants was found reduced in the blind group due to a larger variability of discriminative patterns. In conclusion, our findings suggest that brain plasticity reorganizes the semantic system of blind individuals, and extends semantic computation into the visual cortex.
Closed loop motor-sensory dynamics in human vision
Authors: Gruber Liron , Ahissar Ehud
Published: February 2019

Vision is obtained with a continuous motion of the eyes. The kinematic analysis of eye motion, during any visual or ocular task, typically reveals two (kinematic) components: saccades, which quickly replace the visual content in the retinal fovea, and drifts, which slowly scan the image after each saccade. While the saccadic exchange of regions of interest (ROIs) is commonly considered to be included in motor-sensory closed-loops, it is commonly assumed that drifts function in an open-loop manner, that is, independent of the concurrent visual input. Accordingly, visual perception is assumed to be based on a sequence of open-loop processes, each initiated by a saccade-triggered retinal snapshot. Here we directly challenged this assumption by testing the dependency of drift kinematics on concurrent visual inputs using real-time gaze-contingent-display. Our results demonstrate a dependency of the trajectory on the concurrent visual input, convergence of speed to condition-specific values and maintenance of selected drift-related motor-sensory controlled variables, all strongly indicative of drifts being included in a closed-loop brain-world process, and thus suggesting that vision is inherently a closed-loop process.

Author summary

Our eyes do not function like cameras; it has long been known that we are actively scanning our visual environment in order to see. Moreover, it is commonly accepted that our fast eye movements, saccades, are controlled by the brain and are affected by the sensory input. However, our slow eye movements, the ocular drifts, are often ignored when visual acquisition is analyzed. Accordingly, visual processing is typically assumed to be based on computations performed on saccade-triggered snapshots of the retinal state. Our work strongly challenges this model and provides significant evidence for an alternative model, a cybernetic one. We show that the dynamics of the ocular drifts do not allow, and cannot be explained by, open loop visual acquisition. Instead, our results suggest that visual acquisition is part of a closed-loop process, which dynamically and continuously links the brain to its environment.
PROTEIN THERMAL STABILITY ENGINEERING USING HOTMUSIC
Authors: Pucci Fabrizio , Kwasigroch Jean Marc , Rooman Marianne
Published: February 2019

The rational design of enzymes is a challenging research field, which plays an important role in the optimization of a wide series of biotechnological processes. Computational approaches allow to screen all possible amino acid substitutions in a target protein and to identify a subset likely to have the desired properties. They can thus be used to guide and restrict the huge, time-consuming, search in sequence space to reach protein optimality. Here we present HoTMuSiC, a tool that predicts the impact of point mutations on the protein melting temperature, which uses the experimental or modelled protein structure as sole input, and is available at dezyme.com. Its main advantages include accuracy and speed, which makes it a perfect instrument for thermal stability engineering projects aiming to design new proteins that feature increased heat resistance or remain active and stable in non-physiological conditions. We set up a HoTMuSiC-based pipeline, which uses additional information to avoid mutations of functionally important residues, identified as being too well conserved among homologous proteins or too close to annotated functional sites. The efficiency of this pipeline is successfully demonstrated on Rhizomucor miehei lipase.
Translating antibiotic prescribing into antimicrobial resistance in the environment: a hazard characterisation case study
Authors: Singer Andrew C. , Xu Qiuying , Keller Virginie D.J.
Published: February 2019

The use and misuse of antibiotics in humans, animals and agriculture since penicillin’s mass production in 1942 has contributed to the current global crisis of drug-resistant infections. Often overlooked are the unintended consequences of such widespread antibiotic use, such as the chronic environmental release of unmetabolised, bioactive antibiotics and antibiotic-resistance genes found in human and animals waste, particularly during and immediately after antibiotic treatment. Here, we report on the potential impact on antibiotic resistance gene selection in rivers from the antibiotic prescribing practice of the National Health Service (NHS) of England. Macrolide and fluoroquinolone prescription data from 2015/16 were used to model the concentrations of antibiotics in a highly populous, sewage-impacted English catchment. Predicted antibiotic concentrations in the river were compared against predicted no-effect concentrations (PNEC) to assess the hazard of antibiotic resistance selection. The study revealed that PNECs for macrolides and fluoroquinolones were exceeded in 63% and 73% of the length of the modelled River Thames catchment, respectively. Potential reductions in macrolide and fluoroquinolone prescriptions (e.g., 4% and 20%) were not shown to translate into meaningful reductions in the hazard of AMR selection in the river. Reductions in macrolide and fluoroquinolone prescribing of 77% and 85%, respectively, were necessary to alleviate the AMR selection hazard from 90+% of the modelled river catchment. Improved antibiotic stewardship, alone, is unlikely to alleviate the identified challenge. Action is needed to substantially reduce antibiotic prescribing, stimulate and implement innovation in sewage-treatment, reduce non-antibiotic drivers of antibiotic resistance (e.g., biocides, metals), and consider regulating antibiotic-resistance DNA as a pollutant.
Predicting Empathy from Resting Brain Connectivity
Authors: Christov-Moore Leonardo , Reggente Nicco , Douglas Pamela K. , Feusner Jamie D. , Iacoboni Marco
Published: February 2019

Recent studies suggest that individual differences in empathic concern may be mediated by continuous interactions between self-other resonance and cognitive control networks. To test this hypothesis, we used machine learning to examine whether resting fMRI connectivity (i.e. the degree of synchronous BOLD activity across multiple cortical areas in the absence of task demands) of resonance and control networks could predict trait empathy (n=58). Indeed, resonance and control networks’ interconnectivity predicted empathic concern. Empathic concern was also predicted by connectivity within the somatomotor network. In light of numerous reported sex differences in empathy, we controlled for biological sex and also studied separately what aspect of these features could predict participants’ sex. Sex was best predicted by the interconnectivity of the visual system with the resonance, somatomotor, and cingulo-opercular network, as well as the somatomotor-control network connectivity. These findings confirm that variation in empathic responses to others reflects characteristic network properties detectable regardless of task demands. Furthermore, network properties of the visual system may be a locus of sex differences previously unaccounted for in empathy research. Finally, these findings suggest that it may be possible to assess empathic predispositions in individuals without needing to perform conventional empathy assessments.
Hearing loss promotes schizophrenia-relevant brain and behavioral abnormalities in a mouse model of human 22q11.2 Deletion Syndrome
Authors: Zinnamon Fhatarah A. , Harrison Freya G. , Wenas Sandra S. , Meyer Arne F. , Liu Qing , Wang Kuan Hong , Linden Jennifer F.
Published: February 2019

Hearing loss has been implicated as a risk factor for schizophrenia, but it is not known whether this association arises from common etiology, top-down influences (e.g., social isolation), bottom-up neurobiological mechanisms, or combinations of these factors. Patients with 22q11.2 Deletion Syndrome (22q11.2DS) have a 25-30% risk of developing schizophrenia, and also suffer frequent hearing loss. Here, we used the Df1/+ mouse model of 22q11.2DS to investigate the relationship between hearing loss and susceptibility to schizophrenia-relevant brain and behavioral abnormalities. Df1/+ mice have a multi-gene deletion analogous to the chromosomal microdeletion that causes human 22q11.2DS, and like human 22q11.2DS patients exhibit high rates of hearing loss arising primarily from susceptibility to middle ear inflammation. We found that hearing loss in Df1/+ mice affected schizophrenia-relevant endophenotypes, including electrophysiological measures of central auditory gain and behavioral measures of auditory sensorimotor gating. Moreover, PV+ inhibitory interneurons, another marker for schizophrenia pathology, were significantly reduced in density in auditory cortex but not secondary motor cortex of Df1/+ mice with hearing loss. These results reveal bottom-up neurobiological mechanisms through which peripheral hearing loss arising from the 22q11.2 deletion may promote the emergence of schizophrenia-relevant auditory brain and behavioral abnormalities, and also suggest a link between conductive hearing loss and reduced PV+ interneuron density in the auditory cortex.

SIGNIFICANCE STATEMENT

Hearing loss is a known risk factor for schizophrenia. Deletion of chromosomal locus 22q11.2 is associated with both schizophrenia and hearing loss in humans. In the Df1/+ mouse model of human 22q11.2 Deletion Syndrome, we find that hearing loss shapes measures that are considered schizophrenia-relevant endophenotypes, such as central auditory gain and auditory sensorimotor gating. Moreover, we report a reduction in density of PV+ inhibitory interneurons in the auditory cortex, but not secondary motor cortex, of Df1/+ mice with hearing loss. These results suggest mechanisms through which hearing loss associated with the 22q11.2 deletion may promote emergence of schizophrenia-relevant auditory brain and behavioral abnormalities and indicate that conductive hearing loss may influence PV+ interneuron density in the auditory cortex.
Adaptive stress response induced by toluene increasesSporothrix schenckiivirulence and host immune response
Authors: Téllez-Martínez Damiana , Batista-Duharte Alexander , Silva Vinicius Paschoalini , Fuentes Deivys Portuondo , Ferreira Lucas Souza , Polesi Marisa Campos , Barcelós Costa Caroline , Carlos Iracilda Zeppone
Published: February 2019

Environmental factors modify the physiology of microorganisms, allowing their survival in extreme conditions. However, the influence of chemical contaminants on fungal virulence has been little studied. Sporotrichosis is an emergent fungal disease caused bySporothrix schenckii,a soil-inhabiting fungus that has been found in polluted environments. Here, we evaluated the adaptive stress response ofS. schenckiiinduced by toluene, a key soil contaminant. The effect on fungal virulence and host immune response was also assessed. The fungus survived up to 0.10% toluene in liquid medium. Greater production of melanosomes and enhanced activity superoxide dismutase, associated to increased tolerance to H2O2were observed in toluene-exposed fungi. Intraperitoneal infection of mice withS. schenckiitreated with either 0, 0.01 or 0.1% of toluene, resulted in greater fungal burden at day 7 post-infection in spleen and liver in the groups infected with fungus treated with toluene 0.1%. A higher production of Il-1β, TNF-α, IL-10 and nitric oxyde by peritoneal macrophages and IFNγ, IL-4 and IL-17 by splenocytes was also observed in that group. Our findings showed that morphological and functional changes induced by toluene leads to increasedS. schenckiivirulence and antifungal host immune response in our model.
Cellular heterogeneity during mouse pancreatic ductal adenocarcinoma progression at single-cell resolution
Authors: Hosein Abdel Nasser , Huang Huocong , Wang Zhaoning , Parmar Kamalpreet , Du Wenting , Huang Jonathan , Maitra Anirban , Olson Eric , Verma Udit , Brekken Rolf A.
Published: February 2019

Background & Aims

Pancreatic ductal adenocarcinoma (PDA) is a major cause of cancer-related death with limited therapeutic options available. This highlights the need for improved understanding of the biology of PDA progression. The progression of PDA is a highly complex and dynamic process featuring changes in cancer cells and stromal cells; however, a comprehensive characterization of PDA cancer cell and stromal cell heterogeneity during disease progression is lacking. In this study, we aimed to profile cell populations and understand their phenotypic changes during PDA progression.

Methods

We employed single-cell RNA sequencing technology to agnostically profile cell heterogeneity during different stages of PDA progression in genetically engineered mouse models.

Results

Our data indicate that an epithelial-to-mesenchymal transition of cancer cells accompanies tumor progression. We also found distinct populations of macrophages with increasing inflammatory features during PDA progression. In addition, we noted the existence of three distinct molecular subtypes of fibroblasts in the normal mouse pancreas, which ultimately gave rise to two distinct populations of fibroblasts in advanced PDA, supporting recent reports on intratumoral fibroblast heterogeneity. Our data also suggest that cancer cells and fibroblasts are dynamically regulated by epigenetic mechanisms.

Conclusion

This study systematically outlines the landscape of cellular heterogeneity during the progression of PDA. It strongly improves our understanding of the PDA biology and has the potential to aid in the development of therapeutic strategies against specific cell populations of the disease.
TARGETED, HIGH-RESOLUTION RNA SEQUENCING OF NON-CODING GENOMIC REGIONS ASSOCIATED WITH NEUROPSYCHIATRIC FUNCTIONS
Authors: Hardwick Simon A. , Bassett Samuel D. , Kaczorowski Dominik , Blackburn James , Barton Kirston , Bartonicek Nenad , Carswell Shaun L. , Tilgner Hagen U. , Loy Clement , Halliday Glenda , Mercer Tim R. , Smith Martin A. , Mattick John S.
Published: February 2019

The human brain is one of the last frontiers of biomedical research. Genome-wide association studies (GWAS) have succeeded in identifying thousands of haplotype blocks associated with a range of neuropsychiatric traits, including disorders such as schizophrenia, Alzheimer’s and Parkinson’s disease. However, the majority of single nucleotide polymorphisms (SNPs) that mark these haplotype blocks fall within non-coding regions of the genome, hindering their functional validation. While some of these GWAS loci may contain cis-acting regulatory DNA elements such as enhancers, we hypothesized that many are also transcribed into non-coding RNAs that are missing from publicly available transcriptome annotations. Here, we use targeted RNA capture (‘RNA CaptureSeq’) in combination with nanopore long-read cDNA sequencing to transcriptionally profile 1,023 haplotype blocks across the genome containing non-coding GWAS SNPs associated with neuropsychiatric traits, using post-mortem human brain tissue from three neurologically healthy donors. We find that the majority (62%) of targeted haplotype blocks, including 13% of intergenic blocks, are transcribed into novel, multi-exonic RNAs, most of which are not yet recorded in GENCODE annotations. We validated our findings with short-read RNA-seq, providing orthogonal confirmation of novel splice junctions and enabling a quantitative assessment of the long-read assemblies. Many novel transcripts are supported by independent evidence of transcription including cap analysis of gene expression (CAGE) data and epigenetic marks, and some show signs of potential functional roles. We present these transcriptomes as a preliminary atlas of non-coding transcription in human brain that can be used to connect neurological phenotypes with gene expression.
Quantification of alterations in diffusion measures of white matter integrity associated with healthy aging
Authors: Molloy Ciara J. , Nugent Sinead , Bokde Arun L.W.
Published: February 2019

This study aimed to evaluate the linear association of age with diffusion tensor imaging (DTI) measures of white matter such as fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD). We assessed patterns of overlap between linear correlations of age with FA with RD, MD and AD to characterize the process of white matter degeneration observed with ageing. 79 healthy adults aged between 18 and 75 took part in the study. The DTI data were based on 61 directions acquired with a b-value of 2000. There was a statistically significant negative linear correlation of age with FA and AD and a positive linear correlation with RD and MD, and AD. The forceps minor tract showed largest percentage of voxels with an association of age with FA, RD and AD, and the anterior thalamic radiation with MD. We found 5 main patterns of overlap: FA alone (15.95%); FA and RD (31.90%); FA and AD (12.99%); FA, RD and AD (27.37%); FA RD, and MD (6.94%). Patterns of overlap between diffusion measures may reflect underlying biological changes with healthy ageing such as loss of myelination, axonal damage, as well as mild microstructural and chronic white matter impairments. This study may provide information about causes of degeneration in specific regions of the brain, and how this may affect healthy brain functioning in older adults.
Facilitating Replication and Reproducibility in Team Science: The ‘projects’ R Package
Authors: Krieger Nikolas I. , Perzynski Adam T. , Dalton Jarrod E.
Published: February 2019

The contemporary scientific community places a growing emphasis on the reproducibility of research. TheprojectsR package is a free, open-source endeavor created in the interest of facilitating reproducible research workflows. It adds to existing software tools for reproducible research and introduces several practical features that are helpful for scientists and their collaborative research teams. For each individual project, it supplies an intuitive framework for storing raw and cleaned study data sets, and provides script templates for protocol creation, data cleaning, data analysis and manuscript development. Internal databases of project and author information are generated and displayed, and manuscript title pages containing author lists and their affiliations are automatically generated from the internal database. File management tools allow teams to organize multiple projects. When used on a shared file system, multiple researchers can harmoniously contribute to the same project in a less punctuated manner, reducing the frequency of misunderstandings and the need for status updates.
Effects of decreased Rac activity and malignant state on oral squamous cell carcinoma
Authors: Al-Shareef Hani , Matsuoka Yudai , Kogo Mikihiko , Nakahara Hirokazu
Published: February 2019

Rac proteins, members of the Rho family of small GTP-binding proteins, have been implicated in transducing a number of signals for various biological mechanisms, including cell cytoskeleton organization, transcription, proliferation, migration, and cancer cell motility. Among human cancers, Rac proteins are highly activated by either overexpression of the genes, up-regulation of the protein, or by mutations that allow the protein to elude normal regulatory signaling pathways. Rac proteins are involved in controlling cell survival and apoptosis. The effects of Rac inhibition by the Rac-specific small molecule inhibitor NSC23766 or by transfection of dominant negative Rac (Rac-DN) were examined on three human-derived oral squamous cell carcinoma cell lines that exhibit different malignancy grades, OSC-20 (grade 3), OSC-19 (grade 4C), and HOC313 (grade 4D). Upon suppression of Rac, OSC-19 and HOC313 cells showed significant decreases in Rac activity and resulted in condensation of the nuclei and up- regulation of c-Jun N-terminal kinase (JNK), leading to caspase-dependent apoptosis. In contrast, OSC-20 cells showed only a slight decrease in Rac activity, which resulted in slight activation of JNK and no change in the nuclei. Fibroblasts treated with NSC23766 also showed only a slight decrease in Rac activity with no change in the nuclei or JNK activity. Our results indicated that apoptosis elicited by the inhibition of Rac depended on the extent of decreased Rac activity and the malignant state of the squamous cell carcinoma. In addition, activation of JNK strongly correlated with apoptosis. Rac inhibition may represent a novel therapeutic approach for cancer treatment.
Towards understanding π-stacking interactions between non-aromatic rings
Authors: Molčanov Krešimir , Kojić-Prodić Biserka
Published: February 2019

The first systematic study of π interactions between non-aromatic rings, based on the authors' own results from an experimental X-ray charge-density analysis assisted by quantum chemical calculations, is presented. The landmark (non-aromatic) examples include quinoid rings, planar radicals and metal-chelate rings. The results can be summarized as: (i) non-aromatic planar polyenic rings can be stacked, (ii) interactions are more pronounced between systems or rings with little or no π-electron delocalization (e.g.quinones) than those involving delocalized systems (e.g.aromatics), and (iii) the main component of the interaction is electrostatic/multipolar between closed-shell rings, whereas (iv) interactions between radicals involve a significant covalent contribution (multicentric bonding). Thus, stacking covers a wide range of interactions and energies, ranging from weak dispersion to unlocalized two-electron multicentric covalent bonding (`pancake bonding'), allowing a face-to-face stacking arrangement in some chemical species (quinone anions). The predominant interaction in a particular stacked system modulates the physical properties and defines a strategy for crystal engineering of functional materials.
Cipla-Medpro acquisition: the pre- and post-merger story
Authors: Saxena Nishant , Ungerer Marius
Published: February 2019

Title

Cipla-Medpro acquisition: the pre- and post-merger story.

Learning outcomes

The learning outcomes are as follows: to develop a deeper understanding of the pre- and post-merger factors that should be considered in an M&A transaction; to develop an appreciation of the human capital and organisation cultural aspects involved in cross-country M&A’s; to develop an understanding of the role of leaders and an integration team to make an M&A realise the intended value; and to develop a sensitivity for doing an M&A in a developing country like South Africa.

Case overview/synopsis

This case study creates opportunities for discussing both pre-merger and post-merger dynamics to create a sensitivity that multiple factors contribute to a successful merger and acquisition strategic move. It is intended for classroom discussion only and does not represent correct or incorrect handling of the situation.

Complexity academic level

The complexity is MBA level. This case is primarily focussed on M&A’s as part of a course in Strategic Management (MBA level) but can also be considered for a course on Strategic HRM.

Supplementary materials

Teaching Notes are available for educators only.

Subject code

CSS: 11 Strategy.
Adoption and non-adoption motivational risk beliefs in the use of mobile services for health promotion
Authors: Cocosila Mihail , Turel Ofir
Published: February 2019

Purpose

The purpose of this paper is to validate empirically a theoretical model that integrates an innovative construct capturing consumers’ non-adoption risk belief associated with not using a mobile service designed to support them in a non-leisure activity.

Design/methodology/approach

A theoretical model contrasting perceived non-adoption risk to perceived adoption risk of a mobile service supporting health promotion was developed and tested with a sample of potential consumers in North America.

Findings

Results show that non-adoption risk is a moderately strong antecedent of motivational factors in contrast to adoption risk that hinders the acceptance of a mobile service supporting health promotion.

Research limitations/implications

Healthcare is a highly sensitive social sector, so possible negative consequences of not using the support of a mobile service are an additional motivation for adopting this service. Future research should test the role of non-adoption risk in other contexts of technology use, including non-leisure settings.

Practical implications

Making potential users see the possible negative consequences of not using a mobile service designed to support them in a non-leisure activity increases their motivation and, subsequently, intention to use the service.

Social implications

Educational efforts to making consumers see the risks of not using a supporting technology application appear to be justified.

Originality/value

This study demonstrates the significant role of non-adoption risk belief that captures the negative consequences individuals may perceive if they fail to use as expected a mobile service application designed specifically to help them.
Muslim customer’s shopping experiences in multicultural retail environment
Authors: Ihtiyar Ali
Published: February 2019

Purpose

This study aims to understand better the impact of intercultural communication, social environment and personality on customer satisfaction and post-purchase stage in retailing from Muslim customers’ perspective. In this endeavour, this study illustrates the unique context of intercultural communication to highlight several improvements contributing towards the advancement of intercultural communication literature.

Design/methodology/approach

This research adopted a survey approach where 450 questionnaires were obtained among selected grocery retailers in Klang Valley, Malaysia. The measurement of the constructs and their interrelationships were examined based on partial least squares structural equation modelling (PLS-SEM).

Findings

The findings partially validated the proposed framework with statistically significant relationships among all constructs. Furthermore, it exposed additional insights into some practical and conceptual solutions for addressing intercultural communication of religiously and culturally diverse service encounters in the Malaysian grocery retail industry. These contributions postulated an impetus for future research in various service settings.

Originality/value

Based on the theories, this study assessed the role of the social environment and personality of grocery retail customers on intercultural communication competence (ICC). It also examined the impacts of ICC on inter-role congruence and interaction comfort. It is anticipated that by filling this knowledge gap, the research assisted in strengthening retail communication strategies, which require intercultural communication adjustments in a multicultural business environment. ICC is expected to improve the retail industry’s competitiveness when it positively influences inter-role congruence and interaction comfort among customers.
Investigation of anti‐inflammatory, nitric oxide donating, vasorelaxation and ulcerogenic activities of 1, 3‐diphenylprop‐2‐en‐1‐one derivatives in animal models
Authors: Sherikar Amol , Dhavale Rakesh , Bhatia Manish
Published: February 2019

The main aim of this work is to find out novel chemical moieties with potent anti‐inflammatory and vasorelaxant activities with reduced gastric toxicities. For fulfilling the above aim, here we investigated novel chalcones (1, 3‐diphenylprop‐2‐en‐1‐one derivatives) with nitric oxide (NO) and hydrogen sulphide (H2S) donating potency for anti‐inflammatory activity by carrageenan‐induced rat paw oedema. These molecules then further evaluated for in‐vitro NO‐releasing potency and vasorelaxation effect on isolated adult goat aortic tissue. The promising molecules were further screened for ulcerogenic activity in the rat model. The tested compounds produced % inhibition in paw oedema ranging from 29.16% to 79.69% and standard drug Diclofenac sodium produced 85.30% reduction in paw oedema after 5 hours. Out of this dataset, compounds AI1, AI7, Ca1, B2, B10, D2, and E8 showed 73.01%, 79.69%, 75.02%, 75.46%, 74.35%, 73.9% and 74.35% reduction in paw oedema respectively, which is approximately 80%–90% to that of standard Diclofenac sodium. The compound Ca1 was found to release 0.870 ± 0.025 mol/mol of NO and standard Glyceryl trinitrate (GTN) was found to release 0.983 ± 0.063 mol/mol of NO. The compound Ca1 produced 950.2 μmol/L of EC50 whereas standard GTN produced 975.8 μmol/L of EC50 for aortic smooth relaxation. The compounds Ca1 produced 0.1117 of ulcer index which is far less than that of standard Diclofenac sodium (1.148). The potent lead molecules were further evaluated to understand the mechanism of vasorelaxation by using specific antagonists or blockers of NO and H2S.
From ‘holding pen’ to ‘a space to breathe’: affective landscapes in a newly‐integrated sexual health clinic
Authors: Wright Sarah
Published: February 2019

This paper examines the role of affective landscapes in the formation of attendees’ experiences at a re‐provisioned, integrated sexual and reproductive healthcare facility. The ‘One‐Stop Shop’ (OSS) is an example of the organisational shift towards integrated services occurring across the UK, bringing together in one clinic the historically discreet services of genitourinary medicine, HIV medicine and Family Planning. An ethnographically‐informed study of new spaces of care and changed organisation, this paper focuses on the experiences of 29 attendees as they made their way along the clinic's care pathways. Drawing on concepts of affect and atmosphere to augment the analytic lens of ‘therapeutic landscapes’, this paper demonstrates how various spaces of the clinic influenced attendees’ experiences. A cramped, featureless ‘holding pen’, the foyer served to exacerbate pre‐existing anxieties while creating new fears. The main waiting room, an organisational sorting space, both soothed and aggravated attendees’ concerns. Serving as an architectural feature to connect the old Victorian hospital with the new clinical extension, the atrium was experienced as a space to breathe, with an affective atmosphere that challenged the assumed unpleasantness of sexual health clinics. This paper demonstrates how affective landscapes of the clinic shape attendee experiences in a novel setting.
Inulin addition to yoghurt: Prebiotic activity, health effects and sensory properties
Authors: Esmaeilnejad Moghadam Behnam , Keivaninahr Fatemeh , Fouladi Masoumeh , Rezaei Mokarram Reza , Nazemi Aylar
Published: February 2019

Health and technical aspects of inulin have led to its wide applications in the food industry. Yoghurt is a cultured food with beneficial nutritional value that has advantageous effects in combination with inulin, for example reduction in fat content, improving the functions of the intestinal system and technical and textural influences. In this review, the physicochemical and health properties of inulin are described and also its use as a functional ingredient in yoghurt production is investigated. Also, the ability of inulin to increase probiotic viability and its influence on texture and flavour quality of yoghurt are discussed.