Seven new loci associated with age-related macular degeneration

Age-related macular degeneration (AMD) is a common cause of blindness in older individuals. To accelerate the understanding of AMD biology and help design new therapies, we executed a collaborative genome-wide association study, including >17,100 advanced AMD cases and >60,000 controls of European and Asian ancestry. We identified 19 loci associated at P <5 × 10(-8). These loci show enrichment for genes involved in the regulation of complement activity, lipid metabolism, extracellular matrix remodeling and angiogenesis. Our results include seven loci with associations reaching P <5 × 10(-8) for the first time, near the genes COL8A1-FILIP1L, IER3-DDR1, SLC16A8, TGFBR1, RAD51B, ADAMTS9 and B3GALTL. A genetic risk score combining SNP genotypes from all loci showed similar ability to distinguish cases and controls in all samples examined. Our findings provide new directions for biological, genetic and therapeutic studies of AMD.

Job Strain as a Risk Factor for Leisure-Time Physical Inactivity: An Individual-Participant Meta-Analysis of Up to 170,000 Men and Women

Unfavorable work characteristics, such as low job control and too high or too low job demands, have been suggested to increase the likelihood of physical inactivity during leisure time, but this has not been verified in large-scale studies. The authors combined individual-level data from 14 European cohort studies (baseline years from 19851988 to 20062008) to examine the association between unfavorable work characteristics and leisure-time physical inactivity in a total of 170,162 employees (50 women; mean age, 43.5 years). Of these employees, 56,735 were reexamined after 29 years. In cross-sectional analyses, the odds for physical inactivity were 26 higher (odds ratio 1.26, 95 confidence interval: 1.15, 1.38) for employees with high-strain jobs (low control/high demands) and 21 higher (odds ratio 1.21, 95 confidence interval: 1.11, 1.31) for those with passive jobs (low control/low demands) compared with employees in low-strain jobs (high control/low demands). In prospective analyses restricted to physically active participants, the odds of becoming physically inactive during follow-up were 21 and 20 higher for those with high-strain (odds ratio 1.21, 95 confidence interval: 1.11, 1.32) and passive (odds ratio 1.20, 95 confidence interval: 1.11, 1.30) jobs at baseline. These data suggest that unfavorable work characteristics may have a spillover effect on leisure-time physical activity.

Clonal expansion of hypermutated measles virus in a SSPE brain

Nucleotide sequence analysis was carried out to study genes encoding the matrix (M) protein of measles virus (MV) from several regions of the brain of a case of subacute sclerosing panencephalitis. This analysis revealed the presence of MV with 'wild-type' sequences as well as variants which had undergone at least five biased hypermutation events (U to C and A to G in the positive strand sequences). Despite the presence of MV variants with genes encoding the intact matrix protein open reading frame, M protein could not be detected in any of the brain regions. The distribution of virus variants was studied by cDNA cloning and sequence analysis and by in situ hybridization. The hypermutated viruses appeared to expand clonally throughout the brain of patient B.

Laugh-aware virtual agent and its impact on user amusement

In this paper we present a complete interactive system en- abled to detect human laughs and respond appropriately, by integrating the information of the human behavior and the context. Furthermore, the impact of our autonomous laughter-aware agent on the humor experience of the user and interaction between user and agent is evaluated by sub- jective and objective means. Preliminary results show that the laughter-aware agent increases the humor experience (i.e., felt amusement of the user and the funniness rating of the film clip), and creates the notion of a shared social experience, indicating that the agent is useful to elicit posi- tive humor-related affect and emotional contagion.

Investigations of DNA damage induction and repair resulting from cellular exposure to high dose-rate pulsed proton beams

Studies regarding the radiobiological effects of low dose radiation, microbeam irradiation services have been developed in the world and today laser acceleration of protons and heavy ions may be used in radiation therapy. The application of different facilities is essential for studying bystander effects and relating signalling phenomena in different cells or tissues. In particular the use of ion beams results advantageous in cancer radiotherapy compared to more commonly used X-rays, since the ability of ions in delivering lethal amount of doses into the target tumour avoiding or limiting damage to the contiguous healthy tissues. At the INFN-LNS in Catania, a multidisciplinary radiobiology group is strategically structured aimed to develop radiobiological research, finalised to therapeutic applications, compatible with the use of high dose laser-driven ion beams. The characteristic non-continuous dose rates with several orders of magnitude of laser-driven ion beams makes this facility very interesting in the cellular systems' response to ultra-high dose rates with non-conventional pulse time intervals cellular studies. Our group have projected to examine the effect of high dose laser-driven ion beams on two cellular types: foetal fibroblasts (normal control cells) and DU145 (prostate cancer cells), studying the modulation of some different bio-molecular parameters, in particular cell proliferation and viability, DNA damage, redox cellular status, morphological alterations of both the cytoskeleton components and some cell organelles and the possible presence of apoptotic or necrotic cell death. Our group performed preliminary experiments with high energy (60 MeV), dose rate of 10 Gy/min, doses of 1, 2, 3 Gy and LET 1 keV/µm on human foetal fibroblasts (control cells). We observed that cell viability was not influenced by the characteristics of the beam, the irradiation conditions or the analysis time. Conversely, DNA damage was present at time 0, immediately following irradiation in a dose-dependent manner. The analysis of repair capability showed that the cells irradiated with 1 and 2 Gy almost completely recovered from the damage, but not, however, 3 Gy treated cells in which DNA damage was not recovered. In addition, the results indicate the importance of the use of an appropriate control in radiobiological in vitro analysis.

Laser-ion accelerators: State-of-the-art and scaling laws

A significant amount of experimental work has been devoted over the last decade to the development and optimization of proton acceleration based on the so-called Target Normal Sheath acceleration mechanism. Several studies have been dedicated to the determination of scaling laws for the maximum energy of the protons as a function of the parameters of the irradiating pulses, studies based on experimental results and on models of the acceleration process. We briefly summarize the state of the art in this area, and review some of the scaling studies presented in the literature. We also discuss some recent results, and projected scalings, related to a different acceleration mechanism for ions, based on the Radiation Pressure of an ultraintense laser pulse.

First results on cell irradiation with laser-driven protons on the TARANIS system

The ultra short duration of laser-driven multi-MeV ion bursts offers the possibility of radiobiological studies at extremely high dose rates. Employing the TARANIS Terawatt laser at Queen's University, the effect of proton irradiation at MeV-range energies on live cells has been investigated at dose rates exceeding 10 Gy/s as a single exposure. A clonogenic assay showed consistent lethal effects on V-79 live, cells, which, even at these dose rates, appear to be in line with previously published results employing conventional sources. A Relative Biological Effectiveness (RBE) of 1.4±0.2 at 10% survival is estimated from a comparison with a 225 kVp X-ray source.

Determining the response of African biota to climate change: using the past to model the future

Prediction of biotic responses to future climate change in tropical Africa tends to be based on two modelling approaches: bioclimatic species envelope models and dynamic vegetation models. Another complementary but underused approach is to examine biotic responses to similar climatic changes in the past as evidenced in fossil and historical records. This paper reviews these records and highlights the information that they provide in terms of understanding the local- and regional-scale responses of African vegetation to future climate change. A key point that emerges is that a move to warmer and wetter conditions in the past resulted in a large increase in biomass and a range distribution of woody plants up to 400–500 km north of its present location, the so-called greening of the Sahara. By contrast, a transition to warmer and drier conditions resulted in a reduction in woody vegetation in many regions and an increase in grass/savanna-dominated landscapes. The rapid rate of climate warming coming into the current interglacial resulted in a dramatic increase in community turnover, but there is little evidence for widespread extinctions. However, huge variation in biotic response in both space and time is apparent with, in some cases, totally different responses to the same climatic driver. This highlights the importance of local features such as soils, topography and also internal biotic factors in determining responses and resilience of the African biota to climate change, information that is difficult to obtain from modelling but is abundant in palaeoecological records.

Development of a genotyping microarray for Usher syndrome

Usher syndrome, a combination of retinitis pigmentosa (RP) and sensorineural hearing loss with or without vestibular dysfunction, displays a high degree of clinical and genetic heterogeneity. Three clinical subtypes can be distinguished, based on the age of onset and severity of the hearing impairment, and the presence or absence of vestibular abnormalities. Thus far, eight genes have been implicated in the syndrome, together comprising 347 protein-coding exons.

Screw conveyor device for laboratory tests on conditioned soil for EPB tunneling operations

Earth pressure balanced (EPB) full face tunneling machines have experienced a remarkable increase in the number of applications throughout the world due to both mechanical developments and a more effective use of additives to condition the ground. Conditioning modifies the mechanical and hydraulic properties of a soil by making it suitable for the pressure control in the bulk chamber and extraction with the screw conveyor. The extraction system plays a fundamental role during the EPB operations particularly for a correct application of the face pressure. Despite the extensive use of the EPB technique, little knowledge exists concerning the understanding of the behavior of conditioned soil, particularly for noncohesive ground (sand and gravel). This paper presents and describes a prototype laboratory device, which simulates the extraction of the ground from a pressurized tank with a screw conveyor. The results of a preliminary test program carried out on a medium sized sand show that the prototype device is efficient in verifying the effects of foam for an optimal use in EPB conditioning. © 2007 ASCE.

IntCal13 and Marine13 Radiocarbon Age Calibration Curves 0-50,000 Years Cal BP

The IntCal09 and Marine09 radiocarbon calibration curves have been revised utilizing newly available and updated data sets from C measurements on tree rings, plant macrofossils, speleothems, corals, and foraminifera. The calibration curves were derived from the data using the random walk model (RWM) used to generate IntCal09 and Marine09, which has been revised to account for additional uncertainties and error structures. The new curves were ratified at the 21st International Radiocarbon conference in July 2012 and are available as Supplemental Material at www.radiocarbon.org. The database can be accessed at http://intcal.qub.ac.uk/intcal13/.

Physical and electrochemical evaluation of ATO supported IrO2 catalyst for proton exchange membrane water electrolyser

Antimony doped tin oxide (ATO) was studied as a support material for IrO₂ in proton exchange membrane water electrolyser (PEMWE). Adams fusion method was used to prepare the IrO₂-ATO catalysts. The physical and electrochemical characterisation of the catalysts were carried out using X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), powder conductivity, cyclic voltammetry (CV) and membrane electrode assembly (MEA) polarisation. The BET surface area and electronic conductivity of the supported catalysts were found to be predominantly arisen from the IrO₂. Supported catalyst showed higher active surface area than the pristine IrO₂ in CV analysis with 85% H₃PO₄ as electrolyte. The MEA performance using Nafion®−115 membrane at 80 °C and atmospheric pressure showed a better performance for IrO₂ loading ≥60 wt.% than the pristine IrO₂ with a normalised current density of 1625 mA cm⁻² @1.8 V for the 60% IrO₂-ATO compared to 1341 mA cm⁻² for the pristine IrO₂ under the same condition. The higher performance of the supported catalysts was mainly attributed to better dispersion of active IrO₂ on electrochemically inactive ATO support material, forming smaller IrO₂ crystallites. A 40 wt.% reduction in the IrO₂ was achieved by utilising the support material.

The role of adiposity in cardiometabolic traits:a Mendelian randomization analysis

The association between adiposity and cardiometabolic traits is well known from epidemiological studies. Whilst the causal relationship is clear for some of these traits, for others it is not. We aimed to determine whether adiposity is causally related to various cardiometabolic traits using the Mendelian randomization approach.

Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture

Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.

Anti-TNF antibody-induced psoriasiform skin lesions in patients with inflammatory bowel disease are characterised by interferon-γ-expressing Th1 cells and IL-17A/IL-22-expressing Th17 cells and respond to anti-IL-12/IL-23 antibody treatment

Background We analysed incidence, predictors, histological features and specific treatment options of anti-tumour necrosis factor alpha (TNF-alpha) antibody-induced psoriasiform skin lesions in patients with inflammatory bowel diseases (IBD).

Design Patients with IBD were prospectively screened for anti-TNF-induced psoriasiform skin lesions. Patients were genotyped for IL23R and IL12B variants. Skin lesions were examined for infiltrating Th1 and Th17 cells. Patients with severe lesions were treated with the anti-interleukin (IL)-12/IL-23 p40 antibody ustekinumab.

Results Among 434 anti-TNF-treated patients with IBD, 21 (4.8%) developed psoriasiform skin lesions. Multiple logistic regression revealed smoking (p=0.007; OR 4.24, 95% CI 1.55 to 13.60) and an increased body mass index (p=0.029; OR 1.12, 95% CI 1.01 to 1.24) as main predictors for these lesions. Nine patients with Crohn's disease and with severe psoriasiform lesions and/or anti-TNF antibody-induced alopecia were successfully treated with the anti-p40-IL-12/IL-23 antibody ustekinumab (response rate 100%). Skin lesions were histologically characterised by infiltrates of IL-17A/IL-22-secreting T helper 17 (Th17) cells and interferon (IFN)-gamma-secreting Th1 cells and IFN-alpha-expressing cells. IL-17A expression was significantly stronger in patients requiring ustekinumab than in patients responding to topical therapy (p=0.001). IL23R genotyping suggests disease-modifying effects of rs11209026 (p.Arg381Gln) and rs7530511 (p.Leu310Pro) in patients requiring ustekinumab.

Conclusions New onset psoriasiform skin lesions develop in nearly 5% of anti-TNF-treated patients with IBD. We identified smoking as a main risk factor for developing these lesions. Anti-TNF-induced psoriasiform skin lesions are characterised by Th17 and Th1 cell infiltrates. The number of IL-17A-expressing T cells correlates with the severity of skin lesions. Anti-IL-12/IL23 antibody therapy is a highly effective therapy for these lesions.