Maximizing the good and minimizing the bad: relationships in organizations

In this chapter we introduce the complexities of relationships in organizations, and outline why they are important to study. We discuss the main themes of this book providing a brief overview of the chapters and making links between them. The chapters canvas a wide range of organizational relationships, both positive and fruitful, and dysfunctional and damaging

Prefrontal brain stimulation during food-related inhibition training: effects on food craving, food consumption and inhibitory control

This is the final version. Available on open access from the Royal Society via the DOI in this recordData accessibility: The pre-registered study protocol, anonymised study data and JASP outputs are available on the Open Science Framework (https://osf.io/2597q/).Modulation of dorsolateral prefrontal cortex (DLPFC) activity using non-invasive brain stimulation has been shown to reduce food craving as well as food consumption. Using a preregistered design, we examined whether bilateral transcranial direct current stimulation (tDCS) of the DLPFC could reduce food craving and consumption in healthy participants when administered alongside the cognitive target of inhibitory control training. Participants (N = 172) received either active or sham tDCS (2 mA; anode F4, cathode F3) while completing a food-related Go/No-Go task. State food craving, ad-lib food consumption and response inhibition were evaluated. Compared with sham stimulation, we found no evidence for an effect of active tDCS on any of these outcome measures in a predominantly female sample. Our findings raise doubts about the effectiveness of single-session tDCS on food craving and consumption. Consideration of individual differences, improvements in tDCS protocols and multi-session testing are discussed.Biotechnology and Biological Sciences Research Council (BBSRC)European Research CouncilWellcome Trus

PTEN mutations are common in sporadic microsatellite stable colorectal cancer

The tumour suppressor gene PTEN, located at chromosome sub-band 10q23.3, encodes a dual-specificity phosphatase that negatively regulates the phosphatidylinositol 3′-kinase (PI3 K)/Akt-dependent cellular survival pathway. PTEN is frequently inactivated in many tumour types including glioblastoma, prostate and endometrial cancers. While initial studies reported that PTEN gene mutations were rare in colorectal cancer, more recent reports have shown an approximate 18% incidence of somatic PTEN mutations in colorectal tumours exhibiting microsatellite instability (MSI+). To verify the role of this gene in colorectal tumorigenesis, we analysed paired normal and tumour DNA from 41 unselected primary sporadic colorectal cancers for PTEN inactivation by mutation and/or allelic loss. We now report PTEN gene mutations in 19.5% (8/41) of tumours and allele loss, including all or part of the PTEN gene, in a further 17% (7/41) of the cases. Both PTEN alleles were affected in over half (9/15) of these cases showing PTEN genetic abnormalities. Using immunohistochemistry, we have further shown that all tumours harbouring PTEN alterations have either reduced or absent PTEN expression and this correlated strongly with later clinical stage of tumour at presentation (P = 0.02). In contrast to previous reports, all but one of the tumours with PTEN gene mutations were microsatellite stable (MSI-), suggesting that PTEN is involved in a distinct pathway of colorectal tumorigenesis that is separate from the pathway of mismatch repair deficiency. This work therefore establishes the importance of PTEN in primary sporadic colorectal cancer

Oscillations of aqueous PEDOT:PSS fluid droplets and the properties of complex fluids in drop-on-demand inkjet printing

Shear-thinning aqueous poly(3,4-ethylenedioxythiophene): poly(styrene sulphonate) (PEDOT:PSS) fluids were studied under the conditions of drop-on-demand inkjet printing. Ligament retraction caused oscillation of the resulting drops, from which values of surface tension and viscosity were derived. Effective viscosities of <4 mPa s at drop oscillation frequencies of 13–33 kHz were consistent with conventional high-frequency rheometry, with only a small possible contribution from viscoelasticity with a relaxation time of about 6 μs. Strong evidence was found that the viscosity, reduced by shear-thinning in the printhead nozzle, recovered as the drop formed. The low viscosity values measured for the drops in flight were associated with the strong oscillation induced by ligament retraction, while for a weakly perturbed drop the viscosity remained high. Surface tension values in the presence of surfactant were significantly higher than the equilibrium values, and consistent with the surface age of the drops. [Graphical abstract - see article]This work was supported by EPSRC and a consortium of industrial partners (EPSRC Grant no. EP/H018913/1: Innovation in industrial inkjet technology). The high-speed camera and high power flash lamp were provided by the EPSRC Engineering Instrument Pool and we thank Adrian Walker for his help.This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.jnnfm.2015.05.00

Safe Beacon: A Bluetooth Based Solution to Monitor Egress of Dementia Sufferers within a Residential Setting

The global population is ageing, as a consequence of this there will be a greater incidence of ageing related illnesses which cause cognitive impairment–such as Alzheimer’s disease. Within residential care homes, such cognitive impairment can lead to wandering of individuals beyond the boundaries of safety provided. This wandering, particularly in urban areas can be life threatening. This study introduces a novel solution to detect, and alert caregivers of, egress of at-risk inhabitants of a care home. This solution operates through a combination of wearable Bluetooth beacons and beam-formed listening devices. In an evaluation process involving 275 egress events, this solution proved to offer accurate operation with no incidence of false positives. Notably, this solution has been deployed within a real residential care home environment for over 12 months. Proposed future work discusses improvements to this solution

Islands of conformational stability for Filopodia

Filopodia are long, thin protrusions formed when bundles of fibers grow outwardly from a cell surface while remaining closed in a membrane tube. We study the subtle issue of the mechanical stability of such filopodia and how this depends on the deformation of the membrane that arises when the fiber bundle adopts a helical configuration. We calculate the ground state conformation of such filopodia, taking into account the steric interaction between the membrane and the enclosed semiflexible fiber bundle. For typical filopodia we find that a minimum number of fibers is required for filopodium stability. Our calculation elucidates how experimentally observed filopodia can obviate the classical Euler buckling condition and remain stable up to several tens of . We briefly discuss how experimental observation of the results obtained in this work for the helical-like deformations of enclosing membrane tubes in filopodia could possibly be observed in the acrosomal reactions of the sea cucumber Thyone, and the horseshoe crab Limulus. Any realistic future theories for filopodium stability are likely to rely on an accurate treatment of such steric effects, as analysed in this work

Highly conserved gene order and numerous novel repetitive elements in genomic regions linked to wing pattern variation in Heliconius butterflies

This is the final version of the article. Available from the publisher via the DOI in this record.BACKGROUND: With over 20 parapatric races differing in their warningly colored wing patterns, the butterfly Heliconius erato provides a fascinating example of an adaptive radiation. Together with matching races of its co-mimic Heliconius melpomene, H. erato also represents a textbook case of Müllerian mimicry, a phenomenon where common warning signals are shared amongst noxious organisms. It is of great interest to identify the specific genes that control the mimetic wing patterns of H. erato and H. melpomene. To this end we have undertaken comparative mapping and targeted genomic sequencing in both species. This paper reports on a comparative analysis of genomic sequences linked to color pattern mimicry genes in Heliconius. RESULTS: Scoring AFLP polymorphisms in H. erato broods allowed us to survey loci at approximately 362 kb intervals across the genome. With this strategy we were able to identify markers tightly linked to two color pattern genes: D and Cr, which were then used to screen H. erato BAC libraries in order to identify clones for sequencing. Gene density across 600 kb of BAC sequences appeared relatively low, although the number of predicted open reading frames was typical for an insect. We focused analyses on the D- and Cr-linked H. erato BAC sequences and on the Yb-linked H. melpomene BAC sequence. A comparative analysis between homologous regions of H. erato (Cr-linked BAC) and H. melpomene (Yb-linked BAC) revealed high levels of sequence conservation and microsynteny between the two species. We found that repeated elements constitute 26% and 20% of BAC sequences from H. erato and H. melpomene respectively. The majority of these repetitive sequences appear to be novel, as they showed no significant similarity to any other available insect sequences. We also observed signs of fine scale conservation of gene order between Heliconius and the moth Bombyx mori, suggesting that lepidopteran genome architecture may be conserved over very long evolutionary time scales. CONCLUSION: Here we have demonstrated the tractability of progressing from a genetic linkage map to genomic sequence data in Heliconius butterflies. We have also shown that fine-scale gene order is highly conserved between distantly related Heliconius species, and also between Heliconius and B. mori. Together, these findings suggest that genome structure in macrolepidoptera might be very conserved, and show that mapping and positional cloning efforts in different lepidopteran species can be reciprocally informative.The work was funded by U.S. National Science Foundation grants IOB 0344705 and DEB 0715096 to WOM. The H. erato BAC library was constructed by C. Wu, H. Zhang (TAMU), and M. R. Goldsmith (URI) under NSF Grant IBN-0208388. In addition, the Computational Biology Service Unit at Cornell University, which is partially funded by Microsoft Corporation, provided bioinformatics support for our analysis of genomic repeat structure. AFLP analysis and sequencing of PCR products was carried out at the Sequencing and Genotyping Center at the University of Puerto RicoRio Piedras. We thank Nicola Flanagan, Alexandra Tobler, Karla Maldonado, Jenny Acevedo Gonzales, Hector Alejandro Merchan, Yhadi Cotto, Kelitt Santiago and Felix Araujo Perez for help in rearing and maintaining butterfly stocks. Finally, a special thanks to Daniel P. Lindstrom for his support and helpful suggestions during manuscript preparation

Inositol treatment inhibits medulloblastoma through suppression of epigenetic-driven metabolic adaptation.

Deregulation of chromatin modifiers plays an essential role in the pathogenesis of medulloblastoma, the most common paediatric malignant brain tumour. Here, we identify a BMI1-dependent sensitivity to deregulation of inositol metabolism in a proportion of medulloblastoma. We demonstrate mTOR pathway activation and metabolic adaptation specifically in medulloblastoma of the molecular subgroup G4 characterised by a BMI1High;CHD7Low signature and show this can be counteracted by IP6 treatment. Finally, we demonstrate that IP6 synergises with cisplatin to enhance its cytotoxicity in vitro and extends survival in a pre-clinical BMI1High;CHD7Low xenograft model

Cytoplasmic PML promotes TGF-β-associated epithelial–mesenchymal transition and invasion in prostate cancer

Epithelial–mesenchymal transition (EMT) is a key event that is involved in the invasion and dissemination of cancer cells. Although typically considered as having tumour-suppressive properties, transforming growth factor (TGF)-β signalling is altered during cancer and has been associated with the invasion of cancer cells and metastasis. In this study, we report a previously unknown role for the cytoplasmic promyelocytic leukaemia (cPML) tumour suppressor in TGF-β signalling-induced regulation of prostate cancer-associated EMT and invasion. We demonstrate that cPML promotes a mesenchymal phenotype and increases the invasiveness of prostate cancer cells. This event is associated with activation of TGF-β canonical signalling pathway through the induction of Sma and Mad related family 2 and 3 (SMAD2 and SMAD3) phosphorylation. Furthermore, the cytoplasmic localization of promyelocytic leukaemia (PML) is mediated by its nuclear export in a chromosomal maintenance 1 (CRM1)-dependent manner. This was clinically tested in prostate cancer tissue and shown that cytoplasmic PML and CRM1 co-expression correlates with reduced disease-specific survival. In summary, we provide evidence of dysfunctional TGF-β signalling occurring at an early stage in prostate cancer. We show that this disease pathway is mediated by cPML and CRM1 and results in a more aggressive cancer cell phenotype. We propose that the targeting of this pathway could be therapeutically exploited for clinical benefit

Genomic hotspots for adaptation: the population genetics of Müllerian mimicry in Heliconius erato

This is the final version of the article. Available from the publisher via the DOI in this record.Wing pattern evolution in Heliconius butterflies provides some of the most striking examples of adaptation by natural selection. The genes controlling pattern variation are classic examples of Mendelian loci of large effect, where allelic variation causes large and discrete phenotypic changes and is responsible for both convergent and highly divergent wing pattern evolution across the genus. We characterize nucleotide variation, genotype-by-phenotype associations, linkage disequilibrium (LD), and candidate gene expression patterns across two unlinked genomic intervals that control yellow and red wing pattern variation among mimetic forms of Heliconius erato. Despite very strong natural selection on color pattern, we see neither a strong reduction in genetic diversity nor evidence for extended LD across either patterning interval. This observation highlights the extent that recombination can erase the signature of selection in natural populations and is consistent with the hypothesis that either the adaptive radiation or the alleles controlling it are quite old. However, across both patterning intervals we identified SNPs clustered in several coding regions that were strongly associated with color pattern phenotype. Interestingly, coding regions with associated SNPs were widely separated, suggesting that color pattern alleles may be composed of multiple functional sites, conforming to previous descriptions of these loci as "supergenes." Examination of gene expression levels of genes flanking these regions in both H. erato and its co-mimic, H. melpomene, implicate a gene with high sequence similarity to a kinesin as playing a key role in modulating pattern and provides convincing evidence for parallel changes in gene regulation across co-mimetic lineages. The complex genetic architecture at these color pattern loci stands in marked contrast to the single casual mutations often identified in genetic studies of adaptation, but may be more indicative of the type of genetic changes responsible for much of the adaptive variation found in natural populations.Funding: Funding for this study was provided by National Science Foundation grants to WOM (DEB-0715096 and IBN-0344705) and BAC (DEB-0513424). Funding for work on H. melpomene came from a BBSRC grant to CDJ and RHf-C (011845). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript