Minimal Curvature Trajectories: Riemannian Geometry Concepts for Model Reduction in Chemical Kinetics

In dissipative ordinary differential equation systems different time scales cause anisotropic phase volume contraction along solution trajectories. Model reduction methods exploit this for simplifying chemical kinetics via a time scale separation into fast and slow modes. The aim is to approximate the system dynamics with a dimension-reduced model after eliminating the fast modes by enslaving them to the slow ones via computation of a slow attracting manifold. We present a novel method for computing approximations of such manifolds using trajectory-based optimization. We discuss Riemannian geometry concepts as a basis for suitable optimization criteria characterizing trajectories near slow attracting manifolds and thus provide insight into fundamental geometric properties of multiple time scale chemical kinetics. The optimization criteria correspond to a suitable mathematical formulation of "minimal relaxation" of chemical forces along reaction trajectories under given constraints. We present various geometrically motivated criteria and the results of their application to three test case reaction mechanisms serving as examples. We demonstrate that accurate numerical approximations of slow invariant manifolds can be obtained.Comment: 22 pages, 18 figure

Approximation of slow attracting manifolds in chemical kinetics by trajectory-based optimization approaches

Many common kinetic model reduction approaches are explicitly based on inherent multiple time scales and often assume and directly exploit a clear time scale separation into fast and slow reaction processes. They approximate the system dynamics with a dimension-reduced model after eliminating the fast modes by enslaving them to the slow ones. The corresponding restrictive assumption of full relaxation of fast modes often renders the resulting approximation of slow attracting manifolds inaccurate as a representation of the reduced model and makes the numerical solution of the nonlinear “reduction equations” particularly difficult in many cases where the gap in intrinsic time scales is not large enough. We demonstrate that trajectory optimization approaches can avoid such severe restrictions by computing numerical solutions that correspond to “maximally relaxed” dynamical modes in a suitable sense. We present a framework of trajectory-based optimization for model reduction in chemical kinetics and a general class of reduction criteria characterizing the relaxation of chemical forces along reaction trajectories. These criteria can be motivated geometrically exploiting ideas from differential geometry and fundamental physics and turn out to be highly successful in example applications. Within this framework, we provide results for the computational approximation of slow attracting low-dimensional manifolds in terms of families of optimal trajectories for a six-component hydrogen combustion mechanism

Dose-related efficacy and toxicity of gemtuzumab ozogamicin in pediatric acute myeloid leukemia

Gemtuzumab ozogamicin, an anti-tumour antibiotic linked to an anti-CD33 antibody (Mylotarg®), has been well studied in AML in adults but to a lesser extent in children. No review has yet been published on the dose-related toxicity and efficacy of gemtuzumab ozogamicin in pediatric AML patients. Here we looked at 14 studies then scatterplots and linear regressions were used to estimate the relationship between the dose of gemtuzumab and its toxicity and efficacy. A non-significant increase in bilirubin level and in incidence of veno-occlusive disease was seen with higher doses of gemtuzumab ozogamicin when used as single-agent. In terms of efficacy, even a low dose of 3 mg/m2 of gemtuzumab ozogamicin can have antileukemic effect, but available data do not allow conclusions on its dose-dependency. Data indicate that higher doses of gemtuzumab ozogamicin account for more adverse events. The data do not show that a high dose is required for anti-leukemic efficacy of gemtuzumab ozogamicin. This study also indicates that there seems to be a role for gemtuzumab ozogamicin in the treatment of pediatric AML and further studies are required to assess its optimal dose, schedule and balance between efficacy and side-effects

Adamtsl2 deletion results in bronchial fibrillin microfibril accumulation and bronchial epithelial dysplasia: A novel mouse model providing insights on geleophysic dysplasia

Mutations in the secreted glycoprotein ADAMTSL2 cause recessive geleophysic dysplasia (GD) in humans and Musladin–Lueke syndrome (MLS) in dogs. GD is a severe, often lethal, condition presenting with short stature, brachydactyly, stiff skin, joint contractures, tracheal-bronchial stenosis and cardiac valve anomalies, whereas MLS is non-lethal and characterized by short stature and severe skin fibrosis. Although most mutations in fibrillin-1 (FBN1) cause Marfan syndrome (MFS), a microfibril disorder leading to transforming growth factor-β (TGFβ) dysregulation, domain-specific FBN1 mutations result in dominant GD. ADAMTSL2 has been previously shown to bind FBN1 and latent TGFβ-binding protein-1 (LTBP1). Here, we investigated mice with targeted Adamtsl2 inactivation as a new model for GD (Adamtsl2−/− mice). An intragenic lacZ reporter in these mice showed that ADAMTSL2 was produced exclusively by bronchial smooth muscle cells during embryonic lung development. Adamtsl2−/− mice, which died at birth, had severe bronchial epithelial dysplasia with abnormal glycogen-rich inclusions in bronchial epithelium resembling the cellular anomalies described previously in GD. An increase in microfibrils in the bronchial wall was associated with increased FBN2 and microfibril-associated glycoprotein-1 (MAGP1) staining, whereas LTBP1 staining was increased in bronchial epithelium. ADAMTSL2 was shown to bind directly to FBN2 with an affinity comparable to FBN1. The observed extracellular matrix (ECM) alterations were associated with increased bronchial epithelial TGFβ signaling at 17.5 days of gestation; however, treatment with TGFβ-neutralizing antibody did not correct the epithelial dysplasia. These investigations reveal a new function of ADAMTSL2 in modulating microfibril formation, and a previously unsuspected association with FBN2. Our studies suggest that the bronchial epithelial dysplasia accompanying microfibril dysregulation in Adamtsl2−/− mice cannot be reversed by TGFβ neutralization, and thus might be mediated by other mechanisms

Subtype prediction in pediatric acute myeloid leukemia: Classification using differential network rank conservation revisited

Background: One of the most important application spectrums of transcriptomic data is cancer phenotype classification. Many characteristics of transcriptomic data, such as redundant features and technical artifacts, make over-fitting commonplace. Promising classification results often fail to generalize across datasets with different sources, platforms, or preprocessing. Recently a novel differential network rank conservation (DIRAC) algorithm to characterize cancer phenotypes using transcriptomic data. DIRAC is a member of a family of algorithms that have shown useful for disease classification based on the relative expression of genes. Combining the robustness of this family's simple decision rules with known biological relationships, this systems approach identifies interpretable, yet highly discriminate networks. While DIRAC has been briefly employed for several classification problems in the original paper, the potentials of DIRAC in cancer phenotype classification, and especially robustness against artifacts in transcriptomic data have not been fully characterized yet. Results: In this study we thoroughly investigate the potentials of DIRAC by applying it to multiple datasets, and examine the variations in classification performances when datasets are (i) treated and untreated for batch effect; (ii) preprocessed with different techniques. We also propose the first DIRAC-based classifier to integrate multiple networks. We show that the DIRAC-based classifier is very robust in the examined scenarios. To our surprise, the trained DIRAC-based classifier even translated well to a dataset with different biological characteristics in the presence of substantial batch effects that, as shown here, plagued the standard expression value based classifier. In addition, the DIRAC-based classifier, because of the integrated biological information, also suggests pathways to target in specific subtypes, which may enhance the establishment of personalized therapy in diseases such as pediatric AML. In order to better comprehend the prediction power of the DIRAC-based classifier in general, we also performed classifications using publicly available datasets from breast and lung cancer. Furthermore, multiple well-known classification algorithms were utilized to create an ideal test bed for comparing the DIRAC-based classifier with the standard gene expression value based classifier. We observed that the DIRAC-based classifier greatly outperforms its rival. Conclusions: Based on our experiments with multiple datasets, we propose that DIRAC is a promising solution to the lack of generalizability in classification efforts that uses transcriptomic data. We believe that superior performances presented in this study may motivate other to initiate a new aline of research to explore the untapped power of DIRAC in a broad range of cancer types

Test of Time Dilation Using Stored Li+ Ions as Clocks at Relativistic Speed

We present the concluding result from an Ives-Stilwell-type time dilation experiment using 7Li+ ions confined at a velocity of beta = v/c = 0.338 in the storage ring ESR at Darmstadt. A Lambda-type three-level system within the hyperfine structure of the 7Li+ triplet S1-P2 line is driven by two laser beams aligned parallel and antiparallel relative to the ion beam. The lasers' Doppler shifted frequencies required for resonance are measured with an accuracy of < 4 ppb using optical-optical double resonance spectroscopy. This allows us to verify the Special Relativity relation between the time dilation factor gamma and the velocity beta to within 2.3 ppb at this velocity. The result, which is singled out by a high boost velocity beta, is also interpreted within Lorentz Invariance violating test theories

Physical activity in 9–15 year-old pediatric cancer survivors compared to a nationwide sample

Introduction: Sufficient physical activity (PA) has the potential to mitigate late effects of cancer, but objective data of PA levels in adolescents are scarce. The aim of this study was to investigate differences in PA behavior between childhood cancer survivors (CCS) and healthy peers. Methods: PA levels of n = 74 CCS and n = 1304 healthy peers from the MoMo study aged 9–15 years were assessed with validated objective accelerometry and group means were compared. A binary multiple logistic regression was performed to investigate the potential predictors of PA. Results: CCS spent significantly more time sedentary (p < 0.001) and less time in moderate-to-vigorous physical activity (p = 0.002) compared to the healthy cohort. Subgroup analysis revealed the largest deviations of PA levels for CCS aged 9–11 years who fulfilled international PA recommendations on significantly fewer days than MoMo (p < 0.01). Health conditions seem to be a predictor concerning the fulfillment of international PA recommendations by the WHO (p = 0.015). Conclusions: Our study identified vulnerable groups which seem to require targeted exercise and health behavior change programs to increase physical activity and reduce sedentary time. The presence of treatment sequelae as a significant predictor of insufficient physical activity underlines the need of multidisciplinary supportive care approaches

Characterization and refinement of growth related quantitative trait loci in European sea bass (Dicentrarchus labrax) using a comparative approach

The identification of genetic markers for traits of interest for aquaculture, such as growth, is an important step for the establishment of breeding programmes. As more genomic information becomes available the possibility of applying comparative genomics to identify and refine quantitative trait locus (QTLs) and potentially identify candidate genes responsible for the QTL effect may accelerate genetic improvement in established and new aquaculture species. Here we report such an approach on growth related traits in the European sea bass (Dicentrarchus labrax), an important species for European aquaculture. A genetic map was generated with markers targeted to previously identified QTL for growth which reduced distance and improved resolution in these regions. A total of 36 significant QTLs were identified when morphometric traits were considered individually in maternal half sibs, paternal half sibs and sib-pair analysis. Twenty seven new markers targeted to the growth QTLs, obtained by comparative mapping, reduced the average distance between markers from 23.4, 9.1, and 5.8 cM in the previous map to 3.4, 2.2, and 5.2 cM, on linkage group (LG) LG4, LG6 and LG15 respectively. Lists of genes embedded in the QTL - 591 genes in LG4, 234 genes in LG6 and 450 genes in LG15 - were obtained from the European sea bass genome. Comparative mapping revealed conserved gene synteny across teleost fishes. Functional protein association network analysis with the gene products of the 3 linkage groups revealed a large global association network including 42 gene products. Strikingly the association network was populated with genes of known biological importance for growth and body weight in terrestrial farm animals, such as elements of the signaling pathways for Jak-STAT, MAPK, adipocytokine and insulin, growth hormone, IGFI and II. This study demonstrates the feasibility of a comparative genomics combined with functional gene annotation to refine the resolution of QTL and the establishment of hypothesis to accelerate discovery of putative responsible genes.Statement of relevance: This study demonstrates the feasibility of a comparative genomics approach, combined with functional annotation to refine the resolution of QTL and establishment of hypothesis to accelerate discovery of candidate genes. As production of genomic data is becoming more accessible, the implementation of this strategy will rapidly and efficiently provide the tools required for genetic selection in new candidate aquaculture species. (C) 2016 Elsevier B.V. All rights reserved

GATA1s induces hyperproliferation of eosinophil precursors in Down syndrome transient leukemia

Transient leukemia (TL) is evident in 5–10% of all neonates with Down syndrome (DS) and associated with N-terminal truncating GATA1-mutations (GATA1s). Here we report that TL cell clones generate abundant eosinophils in a substantial fraction of patients. Sorted eosinophils from patients with TL and eosinophilia carried the same GATA1s-mutation as sorted TL-blasts, consistent with their clonal origin. TL-blasts exhibited a genetic program characteristic of eosinophils and differentiated along the eosinophil lineage in vitro. Similarly, ectopic expression of Gata1s, but not Gata1, in wild-type CD34+-hematopoietic stem and progenitor cells induced hyperproliferation of eosinophil promyelocytes in vitro. While GATA1s retained the function of GATA1 to induce eosinophil genes by occupying their promoter regions, GATA1s was impaired in its ability to repress oncogenic MYC and the pro-proliferative E2F transcription network. ChIP-seq indicated reduced GATA1s occupancy at the MYC promoter. Knockdown of MYC, or the obligate E2F-cooperation partner DP1, rescued the GATA1s-induced hyperproliferative phenotype. In agreement, terminal eosinophil maturation was blocked in Gata1Δe2 knockin mice, exclusively expressing Gata1s, leading to accumulation of eosinophil precursors in blood and bone marrow. These data suggest a direct relationship between the N-terminal truncating mutations of GATA1 and clonal eosinophilia in DS patients

Dose selection for radioiodine therapy of borderline hyperthyroid patients according to thyroid uptake of 99mTc-pertechnetate: applicability to unifocal thyroid autonomy?

PURPOSE: The aim of this study was to evaluate the feasibility of applying a previously described dose strategy based on (99m)Tc-pertechnetate thyroid uptake under thyrotropin suppression (TcTU(s)) to radioiodine therapy for unifocal thyroid autonomy. METHODS: A total of 425 consecutive patients (302 females, 123 males; age 63.1+/-10.3 years) with unifocal thyroid autonomy were treated at three different centres with (131)I, using Marinelli's formula for calculation of three different absorbed dose schedules: 100-300 Gy to the total thyroid volume according to the pre-treatment TcTU(s) (n=146), 300 Gy to the nodule volume (n=137) and 400 Gy to the nodule volume (n=142). RESULTS: Successful elimination of functional thyroid autonomy with either euthyroidism or hypothyroidism occurred at a mean of 12 months after radioiodine therapy in 94.5% of patients receiving 100-300 Gy to the thyroid volume, in 89.8% of patients receiving 300 Gy to the nodule volume and in 94.4% receiving 400 Gy to the nodule volume. Reduction in thyroid volume was highest for the 100-300 Gy per thyroid and 400 Gy per nodule strategies (36+/-19% and 38+/-20%, respectively) and significantly lower for the 300 Gy per nodule strategy (28+/-16%; p<0.01). CONCLUSION: A dose strategy based on the TcTU(s) can be used independently of the scintigraphic pattern of functional autonomous tissue in the thyroid