Genome-wide association study reveals three susceptibility loci for common migraine in the general population

Migraine is a common, heterogeneous and heritable neurological disorder. Its pathophysiology is incompletely understood, and its genetic influences at the population level are unknown. In a population-based genome-wide analysis including 5,122 migraineurs and 18,108 non-migraineurs, rs2651899 (1p36.32, PRDM16), rs10166942 (2q37.1, TRPM8) and rs11172113 (12q13.3, LRP1) were among the top seven associations (P < 5 × 10(-6)) with migraine. These SNPs were significant in a meta-analysis among three replication cohorts and met genome-wide significance in a meta-analysis combining the discovery and replication cohorts (rs2651899, odds ratio (OR) = 1.11, P = 3.8 × 10(-9); rs10166942, OR = 0.85, P = 5.5 × 10(-12); and rs11172113, OR = 0.90, P = 4.3 × 10(-9)). The associations at rs2651899 and rs10166942 were specific for migraine compared with non-migraine headache. None of the three SNP associations was preferential for migraine with aura or without aura, nor were any associations specific for migraine features. TRPM8 has been the focus of neuropathic pain models, whereas LRP1 modulates neuronal glutamate signaling, plausibly linking both genes to migraine pathophysiology.

Prognostic value of hTERT mRNA expression in surgical samples of lung cancer patients : the European Early Lung Cancer Project

Lung cancer is the most important cause of cancer-related mortality. Resectability and eligibility for treatment with adjuvant chemotherapy is determined by staging according to the TNM classification. Other determinants of tumour behaviour that predict disease outcome, such as molecular markers, may improve decision-making. Activation of the gene encoding human telomerase reverse transcriptase (hTERT) is implicated in the pathogenesis of lung cancer, and consequently detection of hTERT mRNA might have prognostic value for patients with early stage lung cancer. A cohort of patients who underwent a complete resection for early stage lung cancer was recruited as part of the European Early Lung Cancer (EUELC) project. In 166 patients expression of hTERT mRNA was determined in tumour tissue by quantitative real-time RT-PCR and related to that of a house-keeping gene (PBGD). Of a subgroup of 130 patients tumour-distant normal tissue was additionally available for hTERT mRNA analysis. The correlation between hTERT levels of surgical samples and disease-free survival was determined using a Fine and Gray hazard model. Although hTERT mRNA positivity in tumour tissue was significantly associated with clinical stage (Fisher's exact test p=0.016), neither hTERT mRNA detectability nor hTERT mRNA levels in tumour tissue were associated with clinical outcome. Conversely, hTERT positivity in adjacent normal samples was associated with progressive disease, 28% of patients with progressive disease versus 7.5% of disease-free patients had detectable hTERT mRNA in normal tissue [adjusted HR: 3.60 (1.64-7.94), p=0.0015]. hTERT mRNA level in tumour tissue has no prognostic value for patients with early stage lung cancer. However, detection of hTERT mRNA expression in tumour-distant normal lung tissue may indicate an increased risk of progressive disease.

Business value from intelligent fields

The Smart Fields programme has been active in Shell over the last decade and has given large benefits. In order to understand the value and to underpin strategies for the future implementation programme, a study was carried out to quantify the benefits to date. This focused on actually achieved value, through increased production or lower costs. This provided an estimate of the total value achieved to date. Future benefits such as increased reserves or continued production gain were recorded separately. The paper describes the process followed in the benefits quantification. It identifies the key solutions and technologies and describes the mechanism used to understand the relation between solutions and value. Examples have been given of value from various assets around the world, in both existing fields and in green fields. Finally, the study provided the methodology for tracking of value. This helps Shell to estimate and track the benefits of the Smart Fields programme at company scale.

Comparative susceptibility of mosquito populations in North Queensland, Australia to oral infection with dengue virus

Dengue is the most prevalent arthropod-borne virus, with at least 40% of the world’s population at risk of infection each year. In Australia, dengue is not endemic, but viremic travelers trigger outbreaks involving hundreds of cases. We compared the susceptibility of Aedes aegypti mosquitoes from two geographically isolated populations with two strains of dengue virus serotype 2. We found, interestingly, that mosquitoes from a city with no history of dengue were more susceptible to virus than mosquitoes from an outbreak-prone region, particularly with respect to one dengue strain. These findings suggest recent evolution of population-based differences in vector competence or different historical origins. Future genomic comparisons of these populations could reveal the genetic basis of vector competence and the relative role of selection and stochastic processes in shaping their differences. Lastly, we show the novel finding of a correlation between midgut dengue titer and titer in tissues colonized after dissemination.

Limited dengue virus replication in field-collected Aedes aegypti mosquitoes infected with Wolbachia

Introduction Dengue is one of the most widespread mosquito-borne diseases in the world. The causative agent, dengue virus (DENV), is primarily transmitted by the mosquito Aedes aegypti, a species that has proved difficult to control using conventional methods. The discovery that A. aegypti transinfected with the wMel strain of Wolbachia showed limited DENV replication led to trial field releases of these mosquitoes in Cairns, Australia as a biocontrol strategy for the virus. Methodology/Principal Findings Field collected wMel mosquitoes that were challenged with three DENV serotypes displayed limited rates of body infection, viral replication and dissemination to the head compared to uninfected controls. Rates of dengue infection, replication and dissemination in field wMel mosquitoes were similar to those observed in the original transinfected wMel line that had been maintained in the laboratory. We found that wMel was distributed in similar body tissues in field mosquitoes as in laboratory ones, but, at seven days following blood-feeding, wMel densities increased to a greater extent in field mosquitoes. Conclusions/Significance Our results indicate that virus-blocking is likely to persist in Wolbachia-infected mosquitoes after their release and establishment in wild populations, suggesting that Wolbachia biocontrol may be a successful strategy for reducing dengue transmission in the field.

Theory based production and project management

This paper gives an overview of an ongoing project endeavouring to advance theory-based production and project management, and the rationale for this approach is briefly justified. The status of the theoretical foundation of production management, project management and allied disciplines is discussed, with emphasis on metaphysical grounding of theories, as well as the nature of the heuristic solution method commonly used in these disciplines. Then, on-going work related to different aspects of production and project management is reviewed from both theoretical and practical orientation. Next, information systems agile project management is explored with a view to its re-use in generic project management. In production management, the consequences and implementation of a new, wider theoretical basis are analyzed. The theoretical implications and negative symptoms of the peculiarities of the construction industry for supply chains and supply chain management in construction are observed. Theoretical paths for improvements of inter-organisational relationships in construction which are fundamental for improvement of construction supply chains are described. To conclude, the observations made in this paper vis-à-vis production, project and supply chain management are related again to the theoretical basis of this paper, and finally directions for theory development and future research are given and discussed.

The unfinished revolution : what is missing from the E&P industry’s move to “big data”

One cannot help but be impressed by the inroads that digital oilfield technologies have made into the exploration and production (E&P) industry in the past decade. Today’s production systems can be monitored by “smart” sensors that allow engineers to observe almost any aspect of performance in real time. Our understanding of how reservoirs are behaving has improved considerably since the dawn of this revolution, and the industry has been able to move away from point answers to more holistic “big picture” integrated solutions. Indeed, the industry has already reaped the rewards of many of these kinds of investments. Many billions of dollars of value have been delivered by this heightened awareness of what is going on within our assets and the world around them (Van Den Berg et al. 2010).

Use of the biolistic particle delivery system to transform fungal genomes

Biolistic delivery of transforming DNA into fungal genomes, especially when performed on uninucleate haploid conidia, has proven successful in bypassing the time-consuming repetitive purification of protoplasts used for the widely applied polyethylene glycol-mediated method. Biolistic transformation is also relatively quick compared to other available methods and provides a high percentage of stable transformants.

Activation of forkhead box O transcription factors by oncogenic BRAF promotes p21cip1-dependent senescence

Oncogene-induced senescence (OIS) is a potent tumor-suppressive mechanism that is thought to come at the cost of aging. The Forkhead box O (FOXO) transcription factors are regulators of life span and tumor suppression. However, whether and how FOXOs function in OIS have been unclear. Here, we show a role for FOXO4 in mediating senescence by the human BRAFV600E oncogene, which arises commonly in melanoma. BRAFV600E signaling through mitogen-activated protein kinase/extracellular signal-regulated kinase kinase resulted in increased reactive oxygen species levels and c-Jun NH 2 terminal kinase-mediated activation of FOXO4 via its phosphorylation on Thr223, Ser226, Thr447, and Thr451. BRAFV600E-induced FOXO4 phosphorylation resulted in p21cip1-mediated cell senescence independent of p16 ink4a or p27kip1. Importantly, melanocyte-specific activation of BRAFV600E in vivo resulted in the formation of skin nevi expressing Thr223/Ser226-phosphorylated FOXO4 and elevated p21cip1. Together, these findings support a model in which FOXOs mediate a trade-off between cancer and aging.

Power and paradigms : the Dutch response to pressures for shareholder value

In recent years, research aimed at identifying and relating the antecedents and consequences of diffusing organizational practices/ideas has turned its attention to debating the international adoption and implementation of the Anglo-American model of corporate governance, i.e., a shareholder-value-orientation (SVO). While financial economists characterize the adoption of an SVO as necessary and performance-enhancing, behavioral scientists have disputed such claims, invoking institutional contingencies in the appropriateness of an SVO. Our study seeks to provide some resolution to the debate by developing an overarching socio-political perspective that links the antecedents and consequences of the adoption of the contested practice of SVO. We test our framework using extensive longitudinal data from 1992-2006 from the largest listed corporations in the Netherlands, and we find a negative relationship between SVO adoption and subsequent firm performance, although this effect is attenuated when accompanied by greater SVO-alignment among major owners and a firm’s visible commitment to an SVO. This study extends prior research on the diffusion of contested organizational practices that has taken a socio-political perspective by offering an original contingency perspective that addresses how and why the misaligned preferences of corporate owners will affect (i) a company’s inclination to espouse an SVO, and (ii) the performance consequences of such misalignment.This study suggests when board members are considering the adoption of new ideas/practices (e.g., SVO), they should consider the contextual fitness of the idea/practice with the firm’s owners and their interests.

Roundabout design and cycling safety

Roundabouts reduce the frequency and severity of motor vehicle crashes and therefore the number installed has increased dramatically in the last 20 years in many countries. However, the safety impacts of roundabouts for bicycle riders are a source of concern, with many studies reporting lower injury reductions for cyclists than car occupants. This paper summarises the results of a project undertaken to provide guidance on how cyclist safety could be improved at existing roundabouts in Queensland, Australia, where cyclist crashes have been increasing and legislation gives motor vehicles priority over cyclists and pedestrians at roundabouts. The review of international roundabout design guidelines identified two schools of design: tangential roundabouts (common in English-speaking countries, including Australia), which focus on minimising delay to motor vehicles, and radial roundabouts (common in continental Europe), which focus on speed reduction and safety. While it might be expected that radial roundabouts would be safer for cyclists, there have been no studies to confirm this view. Most guidelines expect cyclists to act as vehicle traffic in single-lane, typically low-speed, roundabouts. Some jurisdictions do not permit cyclists to travel on multi-lane roundabouts, and recommend segregated bicycle facilities because of their lowest crash risk for cyclists. Given that most bicycle-vehicle crashes at roundabouts involve an entering vehicle and a circulating cyclist, the greatest challenges appear to be reducing the speed of motor vehicles on the approach/entry to roundabouts and other ways of maximizing the likelihood that cyclists will be seen. Lower entry speeds are likely to underpin the greater safety of compact roundabouts for cyclists and, conversely, the higher than expected crash rates at two-lane roundabouts. European research discourages the use of bike lanes in roundabouts which position cyclists at the edge of the road and contributes to cyclists being less likely to be noticed by drivers.

Health consequences of exposure to e-waste : a systematic review

Background The population exposed to potentially hazardous substances through inappropriate and unsafe management practices related to disposal and recycling of end-of-life electrical and electronic equipment, collectively known as e-waste, is increasing. We aimed to summarise the evidence for the association between such exposures and adverse health outcomes. Methods We systematically searched five electronic databases (PubMed, Embase, Web of Science, PsycNET, and CINAHL) for studies assessing the association between exposure to e-waste and outcomes related to mental health and neurodevelopment, physical health, education, and violence and criminal behaviour, from Jan 1, 1965, to Dec 17, 2012, and yielded 2274 records. Of the 165 full-text articles assessed for eligibility, we excluded a further 142, resulting in the inclusion of 23 published epidemiological studies that met the predetermined criteria. All studies were from southeast China. We assessed evidence of a causal association between exposure to e-waste and health outcomes within the Bradford Hill framework. Findings We recorded plausible outcomes associated with exposure to e-waste including change in thyroid function, changes in cellular expression and function, adverse neonatal outcomes, changes in temperament and behaviour, and decreased lung function. Boys aged 8–9 years living in an e-waste recycling town had a lower forced vital capacity than did those living in a control town. Significant negative correlations between blood chromium concentrations and forced vital capacity in children aged 11 and 13 years were also reported. Findings from most studies showed increases in spontaneous abortions, stillbirths, and premature births, and reduced birthweights and birth lengths associated with exposure to e-waste. People living in e-waste recycling towns or working in e-waste recycling had evidence of greater DNA damage than did those living in control towns. Studies of the effects of exposure to e-waste on thyroid function were not consistent. One study related exposure to e-waste and waste electrical and electronic equipment to educational outcomes. Interpretation Although data suggest that exposure to e-waste is harmful to health, more well designed epidemiological investigations in vulnerable populations, especially pregnant women and children, are needed to confirm these associations. Funding Children's Health and Environment Program, Queensland Children's Medical Research Institute, The University of Queensland, Australia.

A description of neck motor performance, neck pain, fatigue, and mental effort while driving in a sample with chronic whiplash-associated disorders

Objective: Individuals with chronic whiplash-associated disorders (WADs) often note driving as a difficult task. This study’s aims were to (1) compare, while driving, neck motor performance, mental effort, and fatigue in individuals with chronic WAD against healthy controls and (2) investigate the relationships of these variables and neck pain to self-reported driving difficulty in the WAD group. Design: This study involved 14 participants in each group (WAD and control). Measures included self-reported driving difficulty and measures of neck pain intensity, overall fatigue, mental effort, and neck motor performance (head rotation and upper trapezius activity) while driving a simulator. Results: The WAD group had greater absolute path of head rotation in a simulated city area and used greater mental effort (P = 0.04), but there were no differences in other measures while driving compared with the controls (all P Q 0.05). Self-reported driving difficulty correlated moderately with neck pain intensity, fatigue level, and maximum velocity of head rotation while driving in the WAD group (all P G 0.05). Conclusions: Individuals with chronic WAD do not seem to have impaired neck motor performance while driving yet use greater mental effort. Neck pain, fatigue, and maximum head rotation velocity could be potential contributors to self-reported driving difficulty in this group.

Pituitary volume predicts future transition to psychosis in individuals at ultra-high risk of developing psychosis

Background We examined pituitary volume before the onset of psychosis in subjects who were at ultra-high risk (UHR) for developing psychosis. Methods Pituitary volume was measured on 1.5-mm, coronal, 1.5-T magnetic resonance images in 94 UHR subjects recruited from admissions to the Personal Assessment and Crisis Evaluation Clinic in Melbourne, Australia and in 49 healthy control subjects. The UHR subjects were scanned at baseline and were followed clinically for a minimum of 1 year to detect transition to psychosis. Results Within the UHR group, a larger baseline pituitary volume was a significant predictor of future transition to psychosis. The UHR subjects who later went on to develop psychosis (UHR-P, n = 31) had a significantly larger (+12%; p = .001) baseline pituitary volume compared with UHR subjects who did not go on to develop psychosis (UHR-NP, n = 63). The survival analysis conducted by Cox regression showed that the risk of developing psychosis during the follow-up increased by 20% for every 10% increase in baseline pituitary volume (p = .002). Baseline pituitary volume of the UHR-NP subjects was smaller not only compared with UHR-P (as described above) but also compared with control subjects (−6%; p = .032). Conclusions The phase before the onset of psychosis is associated with a larger pituitary volume, suggesting activation of the HPA axis.

Early maternal deprivation reduces prepulse inhibition and impairs spatial learning ability in adulthood: No further effect of post-pubertal chronic corticosterone treatment

Prolonged maternal deprivation leads to long-term alterations in hypothalamic–pituitary–adrenal (HPA) axis activity, disturbances of auditory information processing and neurochemical changes in the adult brain, some of which are similar to that observed in schizophrenia. Here we report the adult behavioural effects of maternal deprivation (12 h on postnatal days 9 and 11) in Wistar rats on paradigms of auditory information processing (prepulse inhibition), sensitivity to dopamimetics (amphetamine-induced hyper-locomotion) and cognition (T-maze delayed alternation and Morris water-maze). In addition, we examined the long-lasting effect of chronic 21-day corticosterone treatment during the post-pubertal period (i.e., postnatal days 56–76) on each of these behavioural paradigms in maternally deprived and control rats. Behavioural testing commenced 2 weeks after the termination of corticosterone treatment. Maternal deprivation led to a significant reduction in PPI and impaired spatial learning ability in adulthood, but did not affect the behavioural response to amphetamine. Post-pubertal chronic corticosterone treatment did not have any major long-lasting effects on any of the behavioural measures in either maternally deprived or control rats. Our findings further support maternal deprivation as an animal model of specific aspects of schizophrenia.