Maternal urinary metabolic signatures of fetal growth and associated clinical and environmental factors in the INMA study

Background Maternal metabolism during pregnancy is a major determinant of the intra-uterine environment and fetal outcomes. Herein, we characterize the maternal urinary metabolome throughout pregnancy to identify maternal metabolic signatures of fetal growth in two subcohorts and explain potential sources of variation in metabolic profiles based on lifestyle and clinical data. Methods We used 1H nuclear magnetic resonance (NMR) spectroscopy to characterize maternal urine samples collected in the INMA birth cohort at the first (n = 412 and n = 394, respectively, in Gipuzkoa and Sabadell cohorts) and third trimesters of gestation (n = 417 and 469). Metabolic phenotypes that reflected longitudinal intra- and inter-individual variation were used to predict measures of fetal growth and birth weight. Results A metabolic shift between the first and third trimesters of gestation was characterized by 1H NMR signals arising predominantly from steroid by-products. We identified 10 significant and reproducible metabolic associations in the third trimester with estimated fetal, birth, and placental weight in two independent subcohorts. These included branched-chain amino acids; isoleucine, valine, leucine, alanine and 3 hydroxyisobutyrate (metabolite of valine), which were associated with a significant fetal weight increase at week 34 of up to 2.4 % in Gipuzkoa (P < 0.005) and 1 % in Sabadell (P < 0.05). Other metabolites included pregnancy-related hormone by-products of estrogens and progesterone, and the methyl donor choline. We could explain a total of 48–53 % of the total variance in birth weight of which urine metabolites had an independent predictive power of 12 % adjusting for all other lifestyle/clinical factors. First trimester metabolic phenotypes could not predict reproducibly weight at later stages of development. Physical activity, as well as other modifiable lifestyle/clinical factors, such as coffee consumption, vitamin D intake, and smoking, were identified as potential sources of metabolic variation during pregnancy. Conclusions Significant reproducible maternal urinary metabolic signatures of fetal growth and birth weight are identified for the first time and linked to modifiable lifestyle factors. This novel approach to prenatal screening, combining multiple risk factors, present a great opportunity to personalize pregnancy management and reduce newborn disease risk in later life

The BlackHat Library for One-Loop Amplitudes

We present recent next-to-leading order (NLO) results in perturbative QCD obtained using the BlackHat software library. We discuss the use of n-tuples to separate the lengthy matrix-element computations from the analysis process. The use of n-tuples allows many analyses to be carried out on the same phase-space samples, and also allows experimenters to conduct their own analyses using the original NLO computation.Comment: Talk given at ACAT 2013, Beijing, China, May 16--21, 2013; 6 pages, 2 figures; added reference

Universality in W+Multijet Production

We study $W$-boson production accompanied by multiple jets at 7 TeV at the LHC. We study the jet-production ratio, of total cross sections for $W$+$n$- to $W$+($n-1$)-jet production, and the ratio of distributions in the total transverse hadronic jet energy $H_{\rm T}^{\rm jets}$. We use the ratios to extrapolate the total cross section, and the differential distribution in $H_{\rm T}^{\rm jets}$, to $W$+6-jet production. We use the BlackHat software library in conjunction with SHERPA to perform the computations.Comment: Merge of Moriond 2014 and Loops & Legs 2014 proceedings, 6 pages, 2 figure

Interleukin-1 receptor antagonist delivered directly and by gene therapy inhibits matrix degradation in the intact degenerate human intervertebral disc: an in situ zymographic and gene therapy study

Data implicate IL-1 in the altered matrix biology that characterizes human intervertebral disc (IVD) degeneration. In the current study we investigated the enzymic mechanism by which IL-1 induces matrix degradation in degeneration of the human IVD, and whether the IL-1 inhibitor IL-1 receptor antagonist (IL-1Ra) will inhibit degradation. A combination of in situ zymography (ISZ) and immunohistochemistry was used to examine the effects of IL-1 and IL-1Ra on matrix degradation and metal-dependent protease (MDP) expression in explants of non-degenerate and degenerate human IVDs. ISZ employed three substrates (gelatin, collagen, casein) and different challenges (IL-1β, IL-1Ra and enzyme inhibitors). Immunohistochemistry was undertaken for MDPs. In addition, IL-1Ra was introduced into degenerate IVD explants using genetically engineered constructs. The novel findings from this study are: IL-1Ra delivered directly onto explants of degenerate IVDs eliminates matrix degradation as assessed by multi-substrate ISZ; there is a direct relationship between matrix degradation assessed by ISZ and MDP expression defined by immunohistochemistry; single injections of IVD cells engineered to over-express IL-1Ra significantly inhibit MDP expression for two weeks. Our findings show that IL-1 is a key cytokine driving matrix degradation in the degenerate IVD. Furthermore, IL-1Ra delivered directly or by gene therapy inhibits IVD matrix degradation. IL-1Ra could be used therapeutically to inhibit degeneration of the IVD

Mesenchymal stem cell therapies for intervertebral disc degeneration: consideration of the degenerate niche

We have previously reported a synthetic Laponite® crosslinked pNIPAM‐co‐DMAc (NPgel) hydrogel, which induces nucleus pulposus (NP) cell differentiation of human MSCs (hMSCs) without the need for additional growth factors. Furthermore NP gel supports integration following injection into the disc and restores mechanical function to the disc. However, translation of this treatment strategy into clinical application is dependent on the survival and differentiation of hMSC to the correct cell phenotype within the degenerate IVD. Here, we investigated the viability and differentiation of hMSCs within NP gel within a catabolic microenvironment. Human MSCs were encapsulated in NPgel and cultured for 4 weeks under hypoxia (5% O2) with ± calcium, IL‐1β and TNFα either individually or in combination to mimic the degenerate environment. Cell viability, and cellular phenotype was investigated. Stem cell viability was maintained within hydrogel systems for the 4 weeks investigated under all degenerate conditions. NP matrix markers: Agg and Col II and NP phenotypic markers: HIF‐1α, FOXF1 and PAX1 were expressed within the NPgel cultures and expression was not affected by culture within degenerate conditions. Alizarin red staining demonstrated increased calcium deposition under cultures containing CaCl2 indicating calcification of the matrix. Interestingly MMP's, ADAMTS 4 and Col I expression by hMSCs cultured in NPgel was upregulated by calcium but not by pro‐inflammatory cytokines IL‐1β and TNFα. Importantly IL‐1β and TNFα, regarded as key contributors to disc degeneration, were not shown to affect the NP cell differentiation of MSCs in the NPgel. In agreement with our previous findings, NPgel alone was sufficient to induce NP cell differentiation of MSCs, with expression of both aggrecan and collagen type II, under both standard and degenerate culture conditions; thus could provide a therapeutic option for the repair of the NP during IVD degeneration

Next-to-Leading Order Jet Physics with BlackHat

We present several results obtained using the BlackHat next-to-leading order QCD program library, in conjunction with SHERPA. In particular, we present distributions for vector boson plus 1,2,3-jet production at the Tevatron and at the asymptotic running energy of the Large Hadron Collider, including new Z+3-jet distributions. The Z+2-jet predictions for the second-jet P_T distribution are compared to CDF data. We present the jet-emission probability at NLO in W+2-jet events at the LHC, where the tagging jets are taken to be the ones furthest apart in pseudorapidity. We analyze further the large left-handed W polarization, identified in our previous study, for W bosons produced at high P_T at the LHC.Comment: Presented at RADCOR 2009 - 9th International Symposium on Radiative Corrections (Applications of Quantum Field Theory to Phenomenology), October 25 - 30 2009, Ascona, Switzerland}, 12 pages, 9 figures, LaTeX, v2 updated small correction to polarization effect plo

Multi-jet cross sections at NLO with BlackHat and Sherpa

In this talk, we report on a recent next-to-leading order QCD calculation of the production of a W boson in association with three jets at hadron colliders. The computation is performed by combining two programs, BlackHat for the computation of the virtual one-loop matrix elements and Sherpa for the real emission part.Comment: 4 pages, contribution to the proceedings of the XLIIIth Rencontres de Moriond (QCD

Self-Consistency Requirements of the Renormalization Group for Setting the Renormalization Scale

In conventional treatments, predictions from fixed-order perturbative QCD calculations cannot be fixed with certainty due to ambiguities in the choice of the renormalization scale as well as the renormalization scheme. In this paper we present a general discussion of the constraints of the renormalization group (RG) invariance on the choice of the renormalization scale. We adopt the RG based equations, which incorporate the scheme parameters, for a general exposition of RG invariance, since they simultaneously express the invariance of physical observables under both the variation of the renormalization scale and the renormalization scheme parameters. We then discuss the self-consistency requirements of the RG, such as reflexivity, symmetry, and transitivity, which must be satisfied by the scale-setting method. The Principle of Minimal Sensitivity (PMS) requires the slope of the approximant of an observable to vanish at the renormalization point. This criterion provides a scheme-independent estimation, but it violates the symmetry and transitivity properties of the RG and does not reproduce the Gell-Mann-Low scale for QED observables. The Principle of Maximum Conformality (PMC) satisfies all of the deductions of the RG invariance - reflectivity, symmetry, and transitivity. Using the PMC, all non-conformal $\{\beta^{\cal R}_i\}$-terms (${\cal R}$ stands for an arbitrary renormalization scheme) in the perturbative expansion series are summed into the running coupling, and one obtains a unique, scale-fixed, scheme-independent prediction at any finite order. The PMC scales and the resulting finite-order PMC predictions are both to high accuracy independent of the choice of initial renormalization scale, consistent with RG invariance. [...More in the text...]Comment: 15 pages, 4 figures. References updated. To be published in Phys.Rev.

NLO vector boson production with light jets

In this contribution we present recent progress in the computation of next-to-leading order (NLO) QCD corrections for the production of an electroweak vector boson in association with jets at hadron colliders. We focus on results obtained using the virtual matrix element library BLACKHAT in conjunction with SHERPA, focusing on results relevant to understanding the background to top production.Comment: 4+2 epsilon pages, Submitted for the proceedings of TOP2011 - 4th International Workshop on Top Quark Physics, 25-30th September 2011, Sant Feliu de Guixols, Spai