Showing papers by "University of Westminster published in 2017"

Association analysis identifies 65 new breast cancer risk loci

Abstract: Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P < 5 × 10-8. The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.

The New Urban Agenda: key opportunities and challenges for policy and practice

Abstract: The UN-HABITAT III conference held in Quito in late 2016 enshrined the first Sustainable Development Goal (SDG) with an exclusively urban focus. SDG 11, as it became known, aims to make cities more inclusive, safe, resilient and sustainable through a range of metrics, indicators, and evaluation systems. It also became part of a post-Quito ‘New Urban Agenda’ that is still taking shape. This paper raises questions around the potential for reductionism in this new agenda, and argues for the reflexive need to be aware of the types of urban space that are potentially sidelined by the new trends in global urban policy.

Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer.

Abstract: Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P < 5 × 10-8 with ten variants at nine new loci. At P < 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 16% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer.

Do Board’s Corporate Social Responsibility Strategy and Orientation Influence Environmental Sustainability Disclosure? UK Evidence

Abstract: The environmental implications of corporate economic activities have led to growing demands for firms and their boards to adopt sustainable strategies and to disseminate more useful information about their activities and impacts on environment. This paper investigates the impact of board’s corporate social responsibility (CSR) strategy and orientation on the quantity and quality of environmental sustainability disclosure in UK listed firms. We find that effective board CSR strategy and CSR-oriented directors have a positive and significant impact on the quality of environmental sustainability disclosure, but not on the quantity. Our findings also suggest that the existence of a CSR committee and issuance of a stand-alone CSR report are positively and significantly related to environmental sustainability disclosure. When we distinguish between firms with high and low environmental risk, we find that the board CSR/sustainability practices that affect the quantity (quality) of environmental sustainability disclosure appear to be driven more by highly (lowly) environmentally sensitive firms. These results suggest that the board CSR/sustainability practices play an important role in ensuring a firm’s legitimacy and accountability towards stakeholders. Our findings shed new light on this under-researched area and could be of interest to companies, policy-makers and other stakeholders.

Understanding the Impact of E-commerce on Last-Mile Light Goods Vehicle Activity in Urban Areas: The Case of London

Abstract: Growth in e-commerce has led to increasing use of light goods vehicles for parcel deliveries in urban areas. This paper provides an insight into the reasons behind this growth and the resulting effort required to meet the exacting delivery services offered by e-retailers which often lead to poor vehicle utilisation in the last-mile operation, as well as the duplication of delivery services in urban centres as competitors vie for business. A case study investigating current parcel delivery operations in central London identified the scale of the challenge facing the last-mile parcel delivery driver, highlighting the importance of walking which can account for 62% of the total vehicle round time and 40% of the total round distance in the operations studied. The characteristics of these operations are in direct conflict with the urban infrastructure which is being increasingly redesigned in favour of walking, cycling and public transport, reducing the kerbside accessibility for last-mile operations. The paper highlights other pressures on last-mile operators associated with managing seasonal peaks in demand; reduced lead times between customers placing orders and deliveries being made; meeting delivery time windows; first-time delivery failure rates and the need to manage high levels of product returns. It concludes by describing a range of initiatives that retailers and parcel carriers, sometimes in conjunction with city authorities, can implement to reduce the costs associated with last-mile delivery, without negatively impacting on customer service levels.

Whole genome analysis of a schistosomiasis-transmitting freshwater snail.

Abstract: Biomphalaria snails are instrumental in transmission of the human blood fluke Schistosoma mansoni With the World Health Organization's goal to eliminate schistosomiasis as a global health problem by 2025, there is now renewed emphasis on snail control Here, we characterize the genome of Biomphalaria glabrata, a lophotrochozoan protostome, and provide timely and important information on snail biology We describe aspects of phero-perception, stress responses, immune function and regulation of gene expression that support the persistence of B glabrata in the field and may define this species as a suitable snail host for S mansoni We identify several potential targets for developing novel control measures aimed at reducing snail-mediated transmission of schistosomiasis

New developments in tourism and hotel demand modeling and forecasting

Abstract: Purpose The purpose of this paper is to review recent studies published from 2007 to 2015 on tourism and hotel demand modeling and forecasting with a view to identifying the emerging topics and methods studied and to pointing future research directions in the field. Design/methodology/approach Articles on tourism and hotel demand modeling and forecasting published mostly in both science citation index and social sciences citation index journals were identified and analyzed. Findings This review finds that the studies focused on hotel demand are relatively less than those on tourism demand. It is also observed that more and more studies have moved away from the aggregate tourism demand analysis, whereas disaggregate markets and niche products have attracted increasing attention. Some studies have gone beyond neoclassical economic theory to seek additional explanations of the dynamics of tourism and hotel demand, such as environmental factors, tourist online behavior and consumer confidence indicators, among others. More sophisticated techniques such as nonlinear smooth transition regression, mixed-frequency modeling technique and nonparametric singular spectrum analysis have also been introduced to this research area. Research limitations/implications The main limitation of this review is that the articles included in this study only cover the English literature. Future review of this kind should also include articles published in other languages. The review provides a useful guide for researchers who are interested in future research on tourism and hotel demand modeling and forecasting. Practical implications This review provides important suggestions and recommendations for improving the efficiency of tourism and hospitality management practices. Originality/value The value of this review is that it identifies the current trends in tourism and hotel demand modeling and forecasting research and points out future research directions.

The Rise of Resilience

Abstract: As considered in the previous chapter, by the 2010s, there had been a shift towards critical understandings of international peacebuilding approaches which argued that local culture held the key to the impasse of peacebuilding interventions. In this ‘bottom-up’ approach, peace, reconciliation, and a ‘culture of law’ were understood to be secondary effects of sociocultural norms and values. However, these critiques of peacebuilding (the ‘turn to the local’) remained trapped in the impasse of international peacebuilding-as-statebuilding: the inability to go beyond the binaries of liberal universalism (the liberal telos of building ‘peace’) and cultural relativism (the understanding of the barriers to ‘peace’ as an essentialised product of ‘difference’). This understanding will be contrasted in this chapter with an analysis of the rise of ‘resilience’ approaches to intervention – which built on this attention to the particular context of application but moved beyond this impasse through philosophical pragmatism and the positive focus on concrete social practices. This chapter clarifies the nature of this shift through the focus on the shifting understanding of peacebuilding in addressing community conflicts and stresses caused by the failure of ‘war on drugs’ peacebuilding interventions in the Americas.

Chloramidine/Bisindolylmaleimide-I-Mediated Inhibition of Exosome and Microvesicle Release and Enhanced Efficacy of Cancer Chemotherapy

Abstract: Microvesicle (MV) release from tumour cells influences drug retention, contributing to cancer drug resistance. Strategically regulating MV release may increase drug retention within cancer cells and allow for lower doses of chemotherapeutic drugs. The contribution of exosomes to drug retention still remains unknown. Potential exosome and MV (EMV) biogenesis inhibitors, tested on human prostate cancer (PC3) cells for their capacity to inhibit EMV release, were also tested on PC3 and MCF-7 (breast cancer) cells for improving chemotherapy. Agents inhibiting EMV release most significantly, whilst maintaining cell viability, were chloramidine (Cl-amidine; 50 µM) and bisindolylmaleimide-I (10 µM). Apoptosis mediated by the chemotherapy drug 5-fluorouracil (5-FU) was significantly enhanced in PC3 cells in the presence of both these EMV inhibitors, resulting in a 62% (Cl-amidine + 5-FU) and 59% (bisindolylmaleimide-I + 5-FU) decrease in numbers of viable PC3 cells compared to 5-FU alone after 24 h. For MCF-7 cells, there were similar increased reductions of viable cells compared to 5-FU treatment alone ranging from 67% (Cl-amidine + 5-FU) to 58% (bisindolylmaleimide-I + 5-FU). Using combinatory treatment, the two EMV inhibitors further reduced the number of viable cancer cells tested. Neither inhibitor affected cell viability. Combining selected EMV inhibitors may pose as a novel strategy to enhance the efficacy of chemotherapeutic drug-mediated apoptosis.

Automatic selection of molecular descriptors using random forest

Abstract: Random Forest based approach to improve the selection of molecular descriptors.Automatic features selection improves drug discovering methods accuracy.Reduction of complexity and time requirements allows to explore larger datasets. The optimal selection of chemical features (molecular descriptors) is an essential pre-processing step for the efficient application of computational intelligence techniques in virtual screening for identification of bioactive molecules in drug discovery. The selection of molecular descriptors has key influence in the accuracy of affinity prediction. In order to improve this prediction, we examined a Random Forest (RF)-based approach to automatically select molecular descriptors of training data for ligands of kinases, nuclear hormone receptors, and other enzymes. The reduction of features to use during prediction dramatically reduces the computing time over existing approaches and consequently permits the exploration of much larger sets of experimental data. To test the validity of the method, we compared the results of our approach with the ones obtained using manual feature selection in our previous study (Perez-Sanchez, Cano, and Garcia-Rodriguez, 2014).The main novelty of this work in the field of drug discovery is the use of RF in two different ways: feature ranking and dimensionality reduction, and classification using the automatically selected feature subset. Our RF-based method outperforms classification results provided by Support Vector Machine (SVM) and Neural Networks (NN) approaches.

Characterisation of liver fat in the UK Biobank cohort

Abstract: Non-alcoholic fatty liver disease and the risk of progression to steatohepatitis, cirrhosis and hepatocellular carcinoma have been identified as major public health concerns. We have demonstrated the feasibility and potential value of measuring liver fat content by magnetic resonance imaging (MRI) in a large population in this study of 4,949 participants (aged 45–73 years) in the UK Biobank imaging enhancement. Despite requirements for only a single (≤3min) scan of each subject, liver fat was able to be measured as the MRI proton density fat fraction (PDFF) with an overall success rate of 96.4%. The overall hepatic fat distribution was centred between 1–2%, and was highly skewed towards higher fat content. The mean PDFF was 3.91%, and median 2.11%. Analysis of PDFF in conjunction with other data fields available from the UK Biobank Resource showed associations of increased liver fat with greater age, BMI, weight gain, high blood pressure and Type 2 diabetes. Subjects with BMI less than 25 kg/m2 had a low risk (5%) of high liver fat (PDFF > 5.5%), whereas in the higher BMI population (>30 kg/m2) the prevalence of high liver fat was approximately 1 in 3. These data suggest that population screening to identify people with high PDFF is possible and could be cost effective. MRI based PDFF is an effective method for this. Finally, although cross sectional, this study suggests the utility of the PDFF measurement within UK Biobank, particularly for applications to elucidating risk factors through associations with prospectively acquired data on clinical outcomes of liver diseases, including non-alcoholic fatty liver disease.

An examination of the factorial and convergent validity of four measures of conspiracist ideation, with recommendations for researchers

Abstract: A number scales have been developed to measure conspiracist ideation, but little attention has been paid to the factorial validity of these scales. We reassessed the psychometric properties of four widely-used scales, namely the Belief in Conspiracy Theories Inventory (BCTI), the Conspiracy Mentality Questionnaire (CMQ), the Generic Conspiracist Beliefs Scale (GCBS), and the One-Item Conspiracy Measure (OICM). Eight-hundred-and-three U.S. adults completed all measures, along with measures of endorsement of 9/11 and anti-vaccination conspiracy theories. Through both exploratory and confirmatory factor analysis, we found that only the BCTI had acceptable factorial validity. We failed to confirm the factor structures of the CMQ and the GBCS, suggesting these measures had poor factorial validity. Indices of convergent validity were acceptable for the BCTI, but weaker for the other measures. Based on these findings, we provide suggestions for the future refinement in the measurement of conspiracist ideation.

Predictors of clinical recovery from vestibular neuritis: a prospective study

Abstract: We sought to identify predictors of symptomatic recovery in vestibular neuritis. Forty VN patients were prospectively studied in the acute phase (median = 2 days) and 32 in the recovery phase (median = 10 weeks) with vestibulo-ocular reflex, vestibular-perceptual, and visual dependence tests and psychological questionnaires. Clinical outcome was Dizziness Handicap Inventory score at recovery phase. Acute visual dependency and autonomic arousal predicted outcome. Worse recovery was associated with a combination of increased visual dependence, autonomic arousal, anxiety/depression, and fear of bodily sensations, but not with vestibular variables. Findings highlight the importance of early identification of abnormal visual dependency and concurrent anxiety.

From digital positivism and administrative big data analytics towards critical digital and social media research

Abstract: This essay argues for a paradigm shift in the study of the Internet and digital/social media. Big data analytics is the dominant paradigm. It receives large amounts of funding, is administrative and a form of digital positivism. Critical social media research is an alternative approach that combines critical social media theory, critical digital methods and critical-realist social media research ethics. Strengthening the second approach is a material question of power in academia.

Distinct processing of ambiguous speech in people with non-clinical auditory verbal hallucinations.

Abstract: Auditory verbal hallucinations (hearing voices) are typically associated with psychosis, but a minority of the general population also experience them frequently and without distress. Such ‘non-clinical’ experiences offer a rare and unique opportunity to study hallucinations apart from confounding clinical factors, thus allowing for the identification of symptom-specific mechanisms. Recent theories propose that hallucinations result from an imbalance of prior expectation and sensory information, but whether such an imbalance also influences auditory-perceptual processes remains unknown. We examine for the first time the cortical processing of ambiguous speech in people without psychosis who regularly hear voices. Twelve non-clinical voice-hearers and 17 matched controls completed a functional magnetic resonance imaging scan while passively listening to degraded speech (‘sine-wave’ speech), that was either potentially intelligible or unintelligible. Voice-hearers reported recognizing the presence of speech in the stimuli before controls, and before being explicitly informed of its intelligibility. Across both groups, intelligible sine-wave speech engaged a typical left-lateralized speech processing network. Notably, however, voice-hearers showed stronger intelligibility responses than controls in the dorsal anterior cingulate cortex and in the superior frontal gyrus. This suggests an enhanced involvement of attention and sensorimotor processes, selectively when speech was potentially intelligible. Altogether, these behavioural and neural findings indicate that people with hallucinatory experiences show distinct responses to meaningful auditory stimuli. A greater weighting towards prior knowledge and expectation might cause non-veridical auditory sensations in these individuals, but it might also spontaneously facilitate perceptual processing where such knowledge is required. This has implications for the understanding of hallucinations in clinical and non-clinical populations, and is consistent with current ‘predictive processing’ theories of psychosis.

World-wide distributions of lactase persistence alleles and the complex effects of recombination and selection.

Abstract: The genetic trait of lactase persistence (LP) is associated with at least five independent functional single nucleotide variants in a regulatory region about 14 kb upstream of the lactase gene [-13910*T (rs4988235), -13907*G (rs41525747), -13915*G (rs41380347), -14009*G (rs869051967) and -14010*C (rs145946881)]. These alleles have been inferred to have spread recently and present-day frequencies have been attributed to positive selection for the ability of adult humans to digest lactose without risk of symptoms of lactose intolerance. One of the inferential approaches used to estimate the level of past selection has been to determine the extent of haplotype homozygosity (EHH) of the sequence surrounding the SNP of interest. We report here new data on the frequencies of the known LP alleles in the 'Old World' and their haplotype lineages. We examine and confirm EHH of each of the LP alleles in relation to their distinct lineages, but also show marked EHH for one of the older haplotypes that does not carry any of the five LP alleles. The region of EHH of this (B) haplotype exactly coincides with a region of suppressed recombination that is detectable in families as well as in population data, and the results show how such suppression may have exaggerated haplotype-based measures of past selection.

Optimal nutrition and the ever-changing dietary landscape: a conference report.

Abstract: The field of nutrition has evolved rapidly over the past century. Nutrition scientists and policy makers in the developed world have shifted the focus of their efforts from dealing with diseases of overt nutrient deficiency to a new paradigm aimed at coping with conditions of excess—calories, sedentary lifestyles and stress. Advances in nutrition science, technology and manufacturing have largely eradicated nutrient deficiency diseases, while simultaneously facing the growing challenges of obesity, non-communicable diseases and aging. Nutrition research has gone through a necessary evolution, starting with a reductionist approach, driven by an ambition to understand the mechanisms responsible for the effects of individual nutrients at the cellular and molecular levels. This approach has appropriately expanded in recent years to become more holistic with the aim of understanding the role of nutrition in the broader context of dietary patterns. Ultimately, this approach will culminate in a full understanding of the dietary landscape—a web of interactions between nutritional, dietary, social, behavioral and environmental factors—and how it impacts health maintenance and promotion.

Cellular glycosylation affects Herceptin binding and sensitivity of breast cancer cells to doxorubicin and growth factors

Abstract: Alterations in protein glycosylation are a key feature of oncogenesis and have been shown to affect cancer cell behaviour perturbing cell adhesion, favouring cell migration and metastasis. This study investigated the effect of N-linked glycosylation on the binding of Herceptin to HER2 protein in breast cancer and on the sensitivity of cancer cells to the chemotherapeutic agent doxorubicin (DXR) and growth factors (EGF and IGF-1). The interaction between Herceptin and recombinant HER2 protein and cancer cell surfaces (on-rate/off-rate) was assessed using a quartz crystal microbalance biosensor revealing an increase in the accessibility of HER2 to Herceptin following deglycosylation of cell membrane proteins (deglycosylated cells Bmax: 6.83 Hz; glycosylated cells Bmax: 7.35 Hz). The sensitivity of cells to DXR and to growth factors was evaluated using an MTT assay. Maintenance of SKBR-3 cells in tunicamycin (an inhibitor of N-linked glycosylation) resulted in an increase in sensitivity to DXR (0.1 μM DXR P < 0.001) and a decrease in sensitivity to IGF-1 alone and to IGF-1 supplemented with EGF (P < 0.001). This report illustrates the importance of N-linked glycosylation in modulating the response of cancer cells to chemotherapeutic and biological treatments and highlights the potential of glycosylation inhibitors as future combination treatments for breast cancer.

Study on the Pulmonary Delivery System of Apigenin-Loaded Albumin Nanocarriers with Antioxidant Activity.

Abstract: Background: Respiratory diseases are mainly derived from acute and chronic inflammation of the alveoli and bronchi. The pathophysiological mechanisms of pulmonary inflammation mainly arise from oxidative damage that could ultimately lead to acute lung injury. Apigenin (Api) is a natural polyphenol with prominent antioxidant and anti-inflammatory properties in the lung. Inhalable formulations that consist of nanoparticles (NPs) have several advantages over other administration routes, and therefore, this study investigated the application of apigenin-loaded bovine serum albumin nanoparticles (BSA-Api-NPs) for pulmonary delivery. Methods: Dry powder formulations of BSA-Api-NPs were prepared by spray drying and characterized by laser diffraction particle sizing, scanning electron microscopy, differential scanning calorimetry, and powder X-ray diffraction. The influence of dispersibility enhancers (lactose monohydrate and l-leucine) on the in vitro aerosol deposition using a next-generation impactor ...