New genetic loci link adipose and insulin biology to body fat distribution

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.

Genetic studies of body mass index yield new insights for obesity biology

Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

FKBPL: a marker of good prognosis in breast cancer

FK506-binding protein-like (FKBPL) has established roles as an anti-tumor protein, with a therapeutic peptide based on this protein, ALM201, shortly entering phase I/II clinical trials. Here, we evaluated FKBPL's prognostic ability in primary breast cancer tissue, represented on tissue microarrays (TMA) from 3277 women recruited into five independent retrospective studies, using immunohistochemistry (IHC). In a meta-analysis, FKBPL levels were a significant predictor of BCSS; low FKBPL levels indicated poorer breast cancer specific survival (BCSS) (hazard ratio (HR) = 1.30, 95% confidence interval (CI) 1.14-1.49, p < 0.001). The prognostic impact of FKBPL remained significant after adjusting for other known prognostic factors (HR = 1.25, 95% CI 1.07-1.45, p = 0.004). For the sub-groups of 2365 estrogen receptor (ER) positive patients and 1649 tamoxifen treated patients, FKBPL was significantly associated with BCSS (HR = 1.34, 95% CI 1.13-1.58, p < 0.001, and HR = 1.25, 95% CI 1.04-1.49, p = 0.02, respectively). A univariate analysis revealed that FKBPL was also a significant predictor of relapse free interval (RFI) within the ER positive patient group, but it was only borderline significant within the smaller tamoxifen treated patient group (HR = 1.32 95% CI 1.05-1.65, p = 0.02 and HR = 1.23 95% CI 0.99-1.54, p = 0.06, respectively). The data suggests a role for FKBPL as a prognostic factor for BCSS, with the potential to be routinely evaluated within the clinic.

Between Tradition and Modernity: Determining Spatial Systems of Privacy in the Domestic Architecture of Contemporary Iraq

The notion of privacy represents a central criterion for both indoor and outdoor social spaces in most traditional Arab settlements. This paper investigates privacy and everyday life as determinants of the physical properties of the built and urban fabric and will study their impact on traditional settlements and architecture of the home in the contemporary Iraqi city. It illustrates the relationship between socio-cultural aspects of public/private realms using the notion of the social sphere as an investigative tool of the concept of social space in Iraqi houses and local communities (Mahalla). This paper reports that in spite of the impact of other factors in articulating built forms, privacy embodies the primary role under the effects of Islamic rules, principles and culture. The crucial problem is the underestimation of traditional inherited values through opening social spaces to the outside that giving unlimited accesses to the indoor social environment creating many problems with regard to privacy and communal social integration.

Aesthetic Perceptions - Is There a Difference?

Introduction: In recent times, the demand for aesthetic dentistry has increased, with patients presenting for treatment expecting an improvement in their aesthetics. Therefore, it is increasingly important for the dental profession to appreciate perceptions of dental aesthetics in order to provide a patient-centred service.

Objectives: The aim of this study is to quantify perceptions of aesthetics using a cross-sectional survey design. The hypotheses being tested were that differences exist in aesthetic perceptions of 1) dentists and dental students, 2) different age ranges and 3) gender.

Methods: A questionnaire was distributed to dental staff and students in the Cork University Dental School and Hospital. The questionnaire sought information relating to aesthetic perceptions by asking participants to compare photographs of smiles.

Results: 100 questionnaires were returned. It was found that differences existed in perceptions of dentists and dental students when certain aspects of a smile were evaluated, in particular when a minor flaw was present in a smile in addition to the major flaw being tested. Assuming that flaws were detected, more dental students (34%) than dentists (26%) were found to prioritise colour above more subtle flaws, such as a centreline shift. However, most results between the two groups are comparable in terms of their prioritising of importance of particular aspects of a smile, with no large significant differences.

Conclusion: Differences exist in aesthetic perceptions of dentists and dental students, especially with regard to tooth colour.

Cigarette Smoke, Airway Epithelial Cells and Host Defence

In COPD inflammation driven by exposure to tobacco smoke results in impaired innate immunity in the airway and ultimately to lung injury and remodeling. To understand the biological processes involved in host interactions with cigarette derived toxins submerged epithelial cell culture is widely accepted as a model for primary human airway epithelial cell culture research. Primary nasal and bronchial epithelial cells can also be cultured in air-liquid interface (ALI) models. ALI and submerged culture models have their individual merits, and the decision to use either technique should primarily be determined primarily by the research hypothesis.

Cigarette smoke has gaseous and particulate matter, the latter constituent primarily represented in cigarette smoke extract (CSE). Although not ideal in order to facilitate our understanding of the responses of epithelial cells to cigarette smoke, CSE still has scientific merit in airway cell biology research. Using this model, it has been possible to demonstrate differences in levels of tight junction disruption after CSE exposure along with varied vulnerability to the toxic effects of CSE in cell cultures derived from COPD and control study groups.

Primary nasal epithelial cells (PNECs) have been used as an alternative to bronchial epithelial cells (PBECs). However, at least in subjects with COPD, PNECs cannot consistently substitute for PBECs. Although airway epithelial cells from patients with COPD exhibit a constitutional pro-inflammatory phenotype, these cells have a diminished inflammatory response to CSE exposure. COPD epithelial cells have an increased susceptibility to undergo apoptosis, and have reduced levels of Toll-like receptor-4 expression after CSE exposure, both of which may account for the reduced inflammatory response observed in this group.

The use of CSE in both submerged and ALI epithelial cultures has extended our understanding of the cellular mechanisms that are important in COPD, and helped to unravel important pathways which may be of relevance in its pathogenesis.

The Role of Water Content and Paste Proportion on Physico-mechanical Properties of Alkali Activated Fly Ash–Ggbs Concrete

The growth of the construction industry worldwide poses a serious concern on the sustainability of the building material production chain, mainly due to the carbon emissions related to the production of Portland cement. On the other hand, valuable materials from waste streams, particularly from the metallurgical industry, are not used at their full potential. Alkali activated concrete (AAC) has emerged in the last years as a promising alternative to traditional Portland cement based concrete for some applications. However, despite showing remarkable strength and durability potential, its utilisation is not widespread, mainly due to the lack of broadly accepted standards for the selection of suitable mix recipes fulfilling design requirements, in particular workability, setting time and strength. In this paper, a contribution towards the design development of AAC synthetized from pulverised fuel ash (60%) and ground granulated blast furnace slag (40%) activated with a solution of sodium hydroxide and sodium silicate is proposed. Results from a first batch of mixes indicated that water content influences the setting time and that paste content is a key parameter for controlling strength development and workability. The investigation indicated that, for the given raw materials and activator compositions, a minimum water to solid (w/s) ratio of 0.37 was needed for an initial setting time of about 1 hour. Further work with paste content in the range of 30% to 33% determined the relationship between workability and strength development and w/s ratio and paste content. Strengths in the range of 50 - 60 MPa were achieved.

The use of erythropoiesis-stimulating agents with ruxolitinib in patients with myelofibrosis in COMFORT-II: an open-label, phase 3 study assessing efficacy and safety of ruxolitinib versus best available therapy in the treatment of myelofibrosis

BACKGROUND: Anemia is considered a negative prognostic risk factor for survival in patients with myelofibrosis. Most patients with myelofibrosis are anemic, and 35-54 % present with anemia at diagnosis. Ruxolitinib, a potent inhibitor of Janus kinase (JAK) 1 and JAK2, was associated with an overall survival benefit and improvements in splenomegaly and patient-reported outcomes in patients with myelofibrosis in the two phase 3 COMFORT studies. Consistent with the ruxolitinib mechanism of action, anemia was a frequently reported adverse event. In clinical practice, anemia is sometimes managed with erythropoiesis-stimulating agents (ESAs). This post hoc analysis evaluated the safety and efficacy of concomitant ruxolitinib and ESA administration in patients enrolled in COMFORT-II, an open-label, phase 3 study comparing the efficacy and safety of ruxolitinib with best available therapy for treatment of myelofibrosis. Patients were randomized (2:1) to receive ruxolitinib 15 or 20 mg twice daily or best available therapy. Spleen volume was assessed by magnetic resonance imaging or computed tomography scan.

RESULTS: Thirteen of 146 ruxolitinib-treated patients had concomitant ESA administration (+ESA). The median exposure to ruxolitinib was 114 weeks in the +ESA group and 111 weeks in the overall ruxolitinib arm; the median ruxolitinib dose intensity was 33 mg/day for each group. Six weeks before the first ESA administration, 10 of the 13 patients had grade 3/4 hemoglobin abnormalities. These had improved to grade 2 in 7 of the 13 patients by 6 weeks after the first ESA administration. The rate of packed red blood cell transfusions per month within 12 weeks before and after first ESA administration remained the same in 1 patient, decreased in 2 patients, and increased in 3 patients; 7 patients remained transfusion independent. Reductions in splenomegaly were observed in 69 % of evaluable patients (9/13) following first ESA administration.

CONCLUSIONS: Concomitant use of an ESA with ruxolitinib was well tolerated and did not affect the efficacy of ruxolitinib. Further investigations evaluating the effects of ESAs to alleviate anemia in ruxolitinib-treated patients are warranted (ClinicalTrials.gov identifier, NCT00934544; July 6, 2009).

STAT3 regulated ARF expression suppresses prostate cancer metastasis

Prostate cancer (PCa) is the most prevalent cancer in men. Hyperactive STAT3 is thought to be oncogenic in PCa. However, targeting of the IL-6/STAT3 axis in PCa patients has failed to provide therapeutic benefit. Here we show that genetic inactivation of Stat3 or IL-6 signalling in a Pten-deficient PCa mouse model accelerates cancer progression leading to metastasis. Mechanistically, we identify p19(ARF) as a direct Stat3 target. Loss of Stat3 signalling disrupts the ARF-Mdm2-p53 tumour suppressor axis bypassing senescence. Strikingly, we also identify STAT3 and CDKN2A mutations in primary human PCa. STAT3 and CDKN2A deletions co-occurred with high frequency in PCa metastases. In accordance, loss of STAT3 and p14(ARF) expression in patient tumours correlates with increased risk of disease recurrence and metastatic PCa. Thus, STAT3 and ARF may be prognostic markers to stratify high from low risk PCa patients. Our findings challenge the current discussion on therapeutic benefit or risk of IL-6/STAT3 inhibition.

Sustained intraocular VEGF neutralization results in retinal neurodegeneration in the Ins2Akita diabetic mouse

Current therapies that target vascular endothelial growth factor (VEGF) have become a mainstream therapy for the management of diabetic macular oedema. The treatment involves monthly repeated intravitreal injections of VEGF inhibitors. VEGF is an important growth factor for many retinal cells, including different types of neurons. In this study, we investigated the adverse effect of multiple intravitreal anti-VEGF injections (200 ng/μl/eye anti-mouse VEGF164, once every 2 weeks totalling 5-6 injections) to retinal neurons in Ins2(Akita) diabetic mice. Funduscopic examination revealed the development of cotton wool spot-like lesions in anti-VEGF treated Ins2(Akita) mice after 5 injections. Histological investigation showed focal swellings of retinal nerve fibres with neurofilament disruption. Furthermore, anti-VEGF-treated Ins2(Akita) mice exhibited impaired electroretinographic responses, characterized by reduced scotopic a- and b-wave and oscillatory potentials. Immunofluorescent staining revealed impairment of photoreceptors, disruptions of synaptic structures and loss of amacrine and retinal ganglion cells in anti-VEGF treated Ins2(Akita) mice. Anti-VEGF-treated WT mice also presented mild amacrine and ganglion cell death, but no overt abnormalities in photoreceptors and synaptic structures. At the vascular level, exacerbated albumin leakage was observed in anti-VEGF injected diabetic mice. Our results suggest that sustained intraocular VEGF neutralization induces retinal neurodegeneration and vascular damage in the diabetic eye.

Contextual Intrusion Alerts for SCADA Networks

The complexity of modern SCADA networks and their associated cyber-attacks requires an expressive but flexible manner for representing both domain knowledge and collected intrusion alerts with the ability to integrate them for enhanced analytical capabilities and better understanding of attacks. This paper proposes an ontology-based approach for contextualized intrusion alerts in SCADA networks. In this approach, three security ontologies were developed to represent and store information on intrusion alerts, Modbus communications, and Modbus attack descriptions. This information is correlated into enriched intrusion alerts using simple ontology logic rules written in Semantic Query-Enhanced Web Rules (SQWRL). The contextualized alerts give analysts the means to better understand evolving attacks and to uncover the semantic relationships between sequences of individual attack events. The proposed system is illustrated by two use case scenarios.

Secure D2D Communication in Large-Scale Cognitive Cellular Networks: A Wireless Power Transfer Model

In this paper, we investigate secure device-to-device (D2D) communication in energy harvesting large-scale cognitive cellular networks. The energy constrained D2D transmitter harvests energy from multiantenna equipped power beacons (PBs), and communicates with the corresponding receiver using the spectrum of the primary base stations (BSs). We introduce a power transfer model and an information signal model to enable wireless energy harvesting and secure information transmission. In the power transfer model, three wireless power transfer (WPT) policies are proposed: 1) co-operative power beacons (CPB) power transfer, 2) best power beacon (BPB) power transfer, and 3) nearest power beacon (NPB) power transfer. To characterize the power transfer reliability of the proposed three policies, we derive new expressions for the exact power outage probability. Moreover, the analysis of the power outage probability is extended to the case when PBs are equipped with large antenna arrays. In the information signal model, we present a new comparative framework with two receiver selection schemes: 1) best receiver selection (BRS), where the receiver with the strongest channel is selected; and 2) nearest receiver selection (NRS), where the nearest receiver is selected. To assess the secrecy performance, we derive new analytical expressions for the secrecy outage probability and the secrecy throughput considering the two receiver selection schemes using the proposed WPT policies. We presented Monte carlo simulation results to corroborate our analysis and show: 1) secrecy performance improves with increasing densities of PBs and D2D receivers due to larger multiuser diversity gain; 2) CPB achieves better secrecy performance than BPB and NPB but consumes more power; and 3) BRS achieves better secrecy performance than NRS but demands more instantaneous feedback and overhead. A pivotal conclusion- is reached that with increasing number of antennas at PBs, NPB offers a comparable secrecy performance to that of BPB but with a lower complexity.