Candidate gene analysis of femoral neck trabecular and cortical volumetric bone mineral density in older men.

In contrast to conventional dual-energy X-ray absorptiometry, quantitative computed tomography separately measures trabecular and cortical volumetric bone mineral density (vBMD). Little is known about the genetic variants associated with trabecular and cortical vBMD in humans, although both may be important for determining bone strength and osteoporotic risk. In the current analysis, we tested the hypothesis that there are genetic variants associated with trabecular and cortical vBMD at the femoral neck by genotyping 4608 tagging and potentially functional single-nucleotide polymorphisms (SNPs) in 383 bone metabolism candidate genes in 822 Caucasian men aged 65 years or older from the Osteoporotic Fractures in Men Study (MrOS). Promising SNP associations then were tested for replication in an additional 1155 men from the same study. We identified SNPs in five genes (IFNAR2, NFATC1, SMAD1, HOXA, and KLF10) that were robustly associated with cortical vBMD and SNPs in nine genes (APC, ATF2, BMP3, BMP7, FGF18, FLT1, TGFB3, THRB, and RUNX1) that were robustly associated with trabecular vBMD. There was no overlap between genes associated with cortical vBMD and trabecular vBMD. These findings identify novel genetic variants for cortical and trabecular vBMD and raise the possibility that some genetic loci may be unique for each bone compartment

Urban interventionism as a challenge to aesthetic order::Towards an aesthetic criminology

This article is concerned with ideas of urban order and considers the scope for playing with people’s expectations of order. In particular, drawing on criminological, philosophical and urban studies literatures, the article explores the notion of aesthetic order. The power to dictate aesthetic order is highlighted. The example of urban interventionism is used to consider those that challenge an approved aesthetic order. Here the article draws on cultural criminology and visual criminology, with illustrations coming from research in Toronto, Canada. Influenced by Alison Young’s (2014a) conceptualisation of ‘cities within the city’, the article considers how different people using the same space have different or overlapping ways of understanding aesthetic order. Of relevance to criminology, it is contended that people or things that contravene an approved aesthetic order may face banishment and criminalisation. It is concluded that respect for such difference is required. An aesthetic criminology is suggested

Candidate Gene Analysis of Femoral Neck Trabecular and Cortical Volumetric Bone Mineral Density in Older Men

In contrast to conventional dual-energy X-ray absorptiometry, quantitative computed tomography separately measures trabecular and cortical volumetric bone mineral density (vBMD). Little is known about the genetic variants associated with trabecular and cortical vBMD in humans, although both may be important for determining bone strength and osteoporotic risk. In the current analysis, we tested the hypothesis that there are genetic variants associated with trabecular and cortical vBMD at the femoral neck by genotyping 4608 tagging and potentially functional single-nucleotide polymorphisms (SNPs) in 383 bone metabolism candidate genes in 822 Caucasian men aged 65 years or older from the Osteoporotic Fractures in Men Study (MrOS). Promising SNP associations then were tested for replication in an additional 1155 men from the same study. We identified SNPs in five genes (IFNAR2, NFATC1, SMAD1, HOXA, and KLF10) that were robustly associated with cortical vBMD and SNPs in nine genes (APC, ATF2, BMP3, BMP7, FGF18, FLT1, TGFB3, THRB, and RUNX1) that were robustly associated with trabecular vBMD. There was no overlap between genes associated with cortical vBMD and trabecular vBMD. These findings identify novel genetic variants for cortical and trabecular vBMD and raise the possibility that some genetic loci may be unique for each bone compartment. © 2010 American Society for Bone and Mineral Researc

Hypoxia Due to Cardiac Arrest Induces a Time-Dependent Increase in Serum Amyloid β Levels in Humans

Amyloid β (Aβ) peptides are proteolytic products from amyloid precursor protein (APP) and are thought to play a role in Alzheimer disease (AD) pathogenesis. While much is known about molecular mechanisms underlying cerebral Aβ accumulation in familial AD, less is known about the cause(s) of brain amyloidosis in sporadic disease. Animal and postmortem studies suggest that Aβ secretion can be up-regulated in response to hypoxia. We employed a new technology (Single Molecule Arrays, SiMoA) capable of ultrasensitive protein measurements and developed a novel assay to look for changes in serum Aβ42 concentration in 25 resuscitated patients with severe hypoxia due to cardiac arrest. After a lag period of 10 or more hours, very clear serum Aβ42 elevations were observed in all patients. Elevations ranged from approximately 80% to over 70-fold, with most elevations in the range of 3–10-fold (average approximately 7-fold). The magnitude of the increase correlated with clinical outcome. These data provide the first direct evidence in living humans that ischemia acutely increases Aβ levels in blood. The results point to the possibility that hypoxia may play a role in the amyloidogenic process of AD

A Comparison of Mathematical Models for Polarization of Single Eukaryotic Cells in Response to Guided Cues

Polarization, a primary step in the response of an individual eukaryotic cell to a spatial stimulus, has attracted numerous theoretical treatments complementing experimental studies in a variety of cell types. While the phenomenon itself is universal, details differ across cell types, and across classes of models that have been proposed. Most models address how symmetry breaking leads to polarization, some in abstract settings, others based on specific biochemistry. Here, we compare polarization in response to a stimulus (e.g., a chemoattractant) in cells typically used in experiments (yeast, amoebae, leukocytes, keratocytes, fibroblasts, and neurons), and, in parallel, responses of several prototypical models to typical stimulation protocols. We find that the diversity of cell behaviors is reflected by a diversity of models, and that some, but not all models, can account for amplification of stimulus, maintenance of polarity, adaptation, sensitivity to new signals, and robustness

A Historiometric Examination of Machiavellianism and a New Taxonomy of Leadership

Although researchers have extensively examined the relationship between charismatic leadership and Machiavellianism (Deluga, 2001; Gardner & Avolio, 1995; House & Howell, 1992), there has been a lack of investigation of Machiavellianism in relation to alternative forms of outstanding leadership. Thus, the purpose of this investigation was to examine the relationship between Machiavellianism and a new taxonomy of outstanding leadership comprised of charismatic, ideological, and pragmatic leaders. Using an historiometric approach, raters assessed Machiavellianism via the communications of 120 outstanding leaders in organizations across the domains of business, political, military, and religious institutions. Academic biographies were used to assess twelve general performance measures as well as twelve general controls and five communication specific controls. The results indicated that differing levels of Machiavellianism is evidenced across the differing leader types as well as differing leader orientation. Additionally, Machiavellianism appears negatively related to performance, though less so when type and orientation are taken into account.Yeshttps://us.sagepub.com/en-us/nam/manuscript-submission-guideline

Association of the OPRM1 Variant rs1799971 (A118G) with Non-Specific Liability to Substance Dependence in a Collaborative de novo Meta-Analysis of European-Ancestry Cohorts

Peer reviewe

Justify your alpha

Benjamin et al. proposed changing the conventional “statistical significance” threshold (i.e.,the alpha level) from p ≤ .05 to p ≤ .005 for all novel claims with relatively low prior odds. They provided two arguments for why lowering the significance threshold would “immediately improve the reproducibility of scientific research.” First, a p-value near .05provides weak evidence for the alternative hypothesis. Second, under certain assumptions, an alpha of .05 leads to high false positive report probabilities (FPRP2 ; the probability that a significant finding is a false positive

Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes