A joint view on genetic variants for adiposity differentiates subtypes with distinct metabolic implications.

The problem of the genetics of related phenotypes is often addressed by analyzing adjusted-model traits, but such traits warrant cautious interpretation. Here, we adopt a joint view of adiposity traits in ~322,154 subjects (GIANT consortium). We classify 159 signals associated with body mass index (BMI), waist-to-hip ratio (WHR), or WHR adjusted for BMI (WHRadjBMI) at P < 5 × 10 <sup>-8</sup> , into four classes based on the direction of their effects on BMI and WHR. Our classes help differentiate adiposity genetics with respect to anthropometry, fat depots, and metabolic health. Class-specific Mendelian randomization reveals that variants associated with both WHR-decrease and BMI increase are linked to metabolically rather favorable adiposity through beneficial hip fat. Class-specific enrichment analyses implicate digestive systems as a pathway in adiposity genetics. Our results demonstrate that WHRadjBMI variants capture relevant effects of "unexpected fat distribution given the BMI" and that a joint view of the genetics underlying related phenotypes can inform on important biology

An Equivalent Medium Method for the Vacuum Assisted Resin Transfer Molding Process Simulation

Computer simulation has been an efficient and cost-effective tool for liquid composite molding, including resin transfer molding (RTM), vacuum assisted resin transfer molding (VARTM), and resin infusion, compared to trial and error. The control volume finite element method (CVFEM) has been the predominant method for simulation. When the CVFEM simulation is used for the VARTM process, because of the existence of two distinct flow media: fiber preform and high permeable media (HPM), 3-D models are required. Since the HPM is usually much thinner than the fiber preform, a large number of nodes and elements need to be used in simulation, which significantly increases the computation load and time. In addition, the time-consuming preprocessing process makes simulation not feasible for industry applications. This article presents an equivalent medium method (EMM) for fast and accurate VARTM process simulation. This method increases the thickness of the HPM or both the HPM and the fiber preform and applies the equivalent material properties. This is an improved method over previously presented equivalent permeability method (EPM) by correcting its two shortcomings: (1) The EPM does not account for the influence of the porosity of HPM, thus the resin flow through HPM is changed and (2) The EPM does not consider the change of through-thickness permeability after the equivalence. A new mesh generation algorithm is also discussed, which provides a faster and more convenient way for preprocessing. The approach presented in this article provides the fundamental for developing a universal computer simulation tool for both the RTM and VARTM processes. The effectiveness of this approach has been validated by comparing to the conventional CVFEM simulation and experiments

Is there a Jordan geometry underlying quantum physics?

There have been several propositions for a geometric and essentially non-linear formulation of quantum mechanics. From a purely mathematical point of view, the point of view of Jordan algebra theory might give new strength to such approaches: there is a ``Jordan geometry'' belonging to the Jordan part of the algebra of observables, in the same way as Lie groups belong to the Lie part. Both the Lie geometry and the Jordan geometry are well-adapted to describe certain features of quantum theory. We concentrate here on the mathematical description of the Jordan geometry and raise some questions concerning possible relations with foundational issues of quantum theory.Comment: 30 page

Clinical pharmacokinetics and metabolism of irinotecan (CPT-11)

CPT-11 belongs to the class of topoisomerase I inhibitors, and it acts as a prodrug of SN-38, which is approximately 100-1000-fold more cytotoxic than the parent drug. CPT-11 has shown a broad spectrum of antitumor activity in preclinical models as well as clinically, with responses observed in various disease types including colorectal, lung, cervical, and ovarian cancer. The pharmacokinetics and metabolism of CPT-11 are extremely complex and have been the subject of intensive investigation in recent years. Both CPT-11 and SN-38 are known in an active lactone form and an inactive carboxylate form, between which an equilibrium exists that depends on the pH and the presence of binding proteins. CPT-11 is subject to extensive metabolic conversion by various enzyme systems, including esterases to form SN-38, UGT1A1 mediating glucuronidation of SN-38, as well as CYP3A4, which forms several pharmacologically inactive oxidation products. Elimination routes of CPT-11 also depend on the presence of drug-transporting proteins, notably P-glycoprotein and canalicular multispecific organic anion transporter, present on the bile canalicular membrane. The various processes mediating drug elimination, either through metabolic breakdown or excretion, likely impact substantially on interindividual variability in drug handling. Strategies to individualize CPT-11 administration schedules based on patient differences in enzyme or protein expression or by coadministration of specific agents modulating side effects are under way and may ultimately lead to more selective chemotherapeutic use of this agent

Infrared conductivity of a one-dimensional charge-ordered state: quantum lattice effects

The optical properties of the charge-ordering ($CO$) phase of the one-dimensional (1D) half-filled spinless Holstein model are derived at zero temperature within a well-known variational approach improved including second-order lattice fluctuations. Within the $CO$ phase, the static lattice distortions give rise to the optical interband gap, that broadens as the strength of the electron-phonon ($el-ph$) interaction increases. The lattice fluctuation effects induce a long subgap tail in the infrared conductivity and a wide band above the gap energy. The first term is due to the multi-phonon emission by the charge carriers, the second to the interband transitions accompanied by the multi-phonon scattering. The results show a good agreement with experimental spectra.Comment: 5 figure

Testing one-body density functionals on a solvable model

There are several physically motivated density matrix functionals in the literature, built from the knowledge of the natural orbitals and the occupation numbers of the one-body reduced density matrix. With the help of the equivalent phase-space formalism, we thoroughly test some of the most popular of those functionals on a completely solvable model.Comment: Latex, 16 pages, 4 figure

Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels.

Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health

1000 Genomes-based meta-analysis identifies 10 novel loci for kidney function.

HapMap imputed genome-wide association studies (GWAS) have revealed >50 loci at which common variants with minor allele frequency >5% are associated with kidney function. GWAS using more complete reference sets for imputation, such as those from The 1000 Genomes project, promise to identify novel loci that have been missed by previous efforts. To investigate the value of such a more complete variant catalog, we conducted a GWAS meta-analysis of kidney function based on the estimated glomerular filtration rate (eGFR) in 110,517 European ancestry participants using 1000 Genomes imputed data. We identified 10 novel loci with p-value < 5 × 10(-8) previously missed by HapMap-based GWAS. Six of these loci (HOXD8, ARL15, PIK3R1, EYA4, ASTN2, and EPB41L3) are tagged by common SNPs unique to the 1000 Genomes reference panel. Using pathway analysis, we identified 39 significant (FDR < 0.05) genes and 127 significantly (FDR < 0.05) enriched gene sets, which were missed by our previous analyses. Among those, the 10 identified novel genes are part of pathways of kidney development, carbohydrate metabolism, cardiac septum development and glucose metabolism. These results highlight the utility of re-imputing from denser reference panels, until whole-genome sequencing becomes feasible in large samples

Diatreta Cups, Light in Roman Dining Spaces

Cage cups or Diatreta are ancient Roman glass vessels produced by creating a thick blown blank of glass that, once cooled down, is taken to a glass cutter or diatretarii. The latter would cut and carve away most of the glass leaving a transparent vessel inside and an open-work decoration separated through thin posts of glass. The work is very delicate and exclusive, produced within limited space in time with no record of similar vessels until the late 1800 (Donald B. Harden & Toynbee 1959, p.181). Many of these glass objects have good-will inscriptions or decorations that express the importance of drinking. As for their provenance, most –when found in context- have been found in pagan burials. Nevertheless some fragments have been found in Christian environments or with Christian motifs like the Szekszárd cup. The location of these finds is mostly in the Rhine area –northern Empire, when Milan was one of its capitals (Aquaro 2004)- but the actual extent of finds expand throughout the 4th century extent of the Roman Empire. Considering their typological analysis there are basically two types, beaker and bowl. Beakers are considered drinking vessels as they either display a legend or a mythological reference to drink or wine. Whereas a general consensus agrees that open bowl-form cups were hanging lamps (Whitehouse 1988, p.28) since the 1986 find of a diatreta bowl with copper alloy hanging attachments. It is clear these were luxury objects to be used in special occasions and spaces. The aim of this paper is to understand the space were socialisation and drinking took place and the importance of luxurious objects to adorn, display and use. The paper will also put forward the idea that the beaker shaped diatreta vessels, usually considered for drinking, could have been lamps that encouraged drinking and good will to the guests. This paper is structured to first consider an introduction to late luxury Roman glass and then analysing the typological shape of all, or most of the diatreta currently known; secondly, through assessment by the means of comparison, analyse the writings or decorations the vessels were endowed with. Thirdly, by describing and understanding the people and the space were these vessels would have been used, emphasise the beauty of illuminating such spaces with these vessels. According to Herodotus in his historical investigation –5th century-, dress habits and food regime are elements of extreme importance to understand a people (Caporusso et al. 2011, p.12). This idea is not only valid for Herodotus’ time but it is something anthropology uses time and again to explain different aspects in people’s way of life. Through food and its environment, the dining space, this paper will aim to put the cage cups into a social context in order to give emphasis to the hypothesis of light versus wine