Impact of DOTA Conjugation on Pharmacokinetics and Immunoreactivity of [177Lu]Lu-1C1m-Fc, an Anti TEM-1 Fusion Protein Antibody in a TEM-1 Positive Tumor Mouse Model.

1C1m-Fc, an anti-tumor endothelial marker 1 (TEM-1) scFv-Fc fusion protein antibody, was previously successfully radiolabeled with <sup>177</sup> Lu. TEM-1 specific tumor uptake was observed together with a non-saturation dependent liver uptake that could be related to the number of dodecane tetraacetic acid (DOTA) chelator per 1C1m-Fc. The objective of this study was to verify this hypothesis and to find the best DOTA per 1C1m-Fc ratio for theranostic applications. 1C1m-Fc was conjugated with six concentrations of DOTA. High-pressure liquid chromatography, mass spectrometry, immunoreactivity assessment, and biodistribution studies in mice bearing TEM-1 positive tumors were performed. A multi-compartment pharmacokinetic model was used to fit the data and a global pharmacokinetic model was developed to illustrate the effect of liver capture and immunoreactivity loss. Organ absorbed doses in mice were calculated from biodistribution results. A loss of immunoreactivity was observed with the highest DOTA per 1C1m-Fc ratio. Except for the spleen and bone, an increase of DOTA per 1C1m-Fc ratio resulted in an increase of liver uptake and absorbed dose and a decrease of uptake in tumor and other tissues. Pharmacokinetic models correlated these results. The number of DOTA per antibody played a determining role in tumor targeting. One DOTA per 1C1m-Fc gave the best pharmacokinetic behavior for a future translation of [ <sup>177</sup> Lu]Lu-1C1m-Fc in patients

Nanofriction mechanisms derived from the dependence of friction on load and sliding velocity from air to UHV on hydrophilic silicon

This paper examines friction as a function of the sliding velocity and applied normal load from air to UHV in a scanning force microscope (SFM) experiment in which a sharp silicon tip slides against a flat Si(100) sample. Under ambient conditions, both surfaces are covered by a native oxide, which is hydrophilic. During pump-down in the vacuum chamber housing the SFM, the behavior of friction as a function of the applied normal load and the sliding velocity undergoes a change. By analyzing these changes it is possible to identify three distinct friction regimes with corresponding contact properties: (a) friction dominated by the additional normal forces induced by capillarity due to the presence of thick water films, (b) higher drag force from ordering effects present in thin water layers and (c) low friction due to direct solid-solid contact for the sample with the counterbody. Depending on environmental conditions and the applied normal load, all three mechanisms may be present at one time. Their individual contributions can be identified by investigating the dependence of friction on the applied normal load as well as on the sliding velocity in different pressure regimes, thus providing information about nanoscale friction mechanisms

Predicting local and non-local effects of resources on animal space use using a mechanistic step selection model

1. Predicting space use patterns of animals from their interactions with the environment is fundamental for understanding the effect of habitat changes on ecosystem functioning. Recent attempts to address this problem have sought to unify resource selection analysis, where animal space use is derived from available habitat quality, and mechanistic movement models, where detailed movement processes of an animal are used to predict its emergent utilization distribution. Such models bias the animal's movement towards patches that are easily available and resource-rich, and the result is a predicted probability density at a given position being a function of the habitat quality at that position. However, in reality, the probability that an animal will use a patch of the terrain tends to be a function of the resource quality in both that patch and the surrounding habitat. 2. We propose a mechanistic model where this non-local effect of resources naturally emerges from the local movement processes, by taking into account the relative utility of both the habitat where the animal currently resides and that of where it is moving. We give statistical techniques to parametrize the model from location data and demonstrate application of these techniques to GPS data of caribou in Newfoundland. 3. Steady-state animal probability distributions arising from the model have complex patterns that cannot be expressed simply as a function of the local quality of the habitat. In particular, large areas of good habitat are used more intensively than smaller patches of equal quality habitat, whereas isolated patches are used less frequently. 4. Whilst we focus on habitats in this study, our modelling framework can be readily used with any environmental covariates and therefore represents a unification of mechanistic modelling and step selection approaches to understanding animal space use

A lattice calculation of vector meson couplings to the vector and tensor currents using chirally improved fermions

We present a quenched lattice calculation of $f_V^\perp/f_V$, the coupling of vector mesons to the tensor current normalized by the vector meson decay constant. The chirally improved lattice Dirac operator, which allows us to reach small quark masses, is used. We put emphasis on analyzing the quark mass dependence of $f_V^\perp/f_V$ and find only a rather weak dependence. Our results at the $\rho$ and $\phi$ masses agree well with QCD sum rule calculations and those from previous lattice studies.Comment: 6 pages, 3 figures, one sentence remove

Refining human palaeodietary reconstruction using amino acid delta N-15 values of plants, animals and humans.

An established method of estimating the trophic level of an organism is through stable isotope analysis of its tissues and those of its diet. This method has been used in archaeology to reconstruct past human diet from the stable nitrogen isotope (d15N) values of human and herbivore bone collagen. However, this approach, using the 15N-enrichment of human bone collagen d15N values over associated herbivore bone collagen d15N values to predict the relative importance of animal protein, relies on the assumptions that: (i) the d15N values of plants consumed by humans and herbivores are identical, and (ii) the 15Nenrichment between diet and consumer is consistent. Bone collagen amino acid d15N values have the potential to tackle these uncertainties, as they constrain the factors influencing bone collagen d15N values. In this study, the d15N values of glutamic acid and phenylalanine in human and herbivore bone collagen isolates from Neolithic sites in Germany, Greece and Turkey were determined by gas chromatography-combustion-isotope ratio mass spectrometry. The fraction of animal protein in total dietary protein consumed by the humans was estimated by: (i) comparing bulk human and herbivore collagen d15N values, (ii) comparing bulk human and herbivore collagen and ancient charred cereal grain d15N values, (iii) comparing human bone collagen d15NGlutamic acid and d15NPhenylalanine values, and (iv) comparing d15NGlutamic acid values of human and herbivore bone collagen and estimated d15NGlutamic acid values of ancient charred cereal grains. Where determined cereal grain d15N values are higher than estimated herbivore forage values, estimates of animal protein consumption are significantly lower, emphasising the importance of the plant nitrogen contribution to human bone collagen. This study also highlights the need for further investigation into: (i) the D15NConsumer-Diet values of glutamic acid and phenylalanine in terrestrial ecosystems, and (ii) D15NGlutamic acid-Phenylalanine values of common plant foods in order to improve the accuracy and more widespread applicability of amino acid-based methods for palaeodietary reconstruction

Constraining warm dark matter with cosmic shear power spectra

We investigate potential constraints from cosmic shear on the dark matter particle mass, assuming all dark matter is made up of light thermal relic particles. Given the theoretical uncertainties involved in making cosmological predictions in such warm dark matter scenarios we use analytical fits to linear warm dark matter power spectra and compare (i) the halo model using a mass function evaluated from these linear power spectra and (ii) an analytical fit to the non-linear evolution of the linear power spectra. We optimistically ignore the competing effect of baryons for this work. We find approach (ii) to be conservative compared to approach (i). We evaluate cosmological constraints using these methods, marginalising over four other cosmological parameters. Using the more conservative method we find that a Euclid-like weak lensing survey together with constraints from the Planck cosmic microwave background mission primary anisotropies could achieve a lower limit on the particle mass of 2.5 keV.Comment: 26 pages, 9 figures, minor changes to match the version accepted for publication in JCA

Required knowledge for guideline panel members to develop healthcare related testing recommendations:a developmental study

Objectives: To define the minimum knowledge required for guideline panel members (healthcare professionals and consumers) involved in developing recommendations about healthcare related testing. Study Design and Setting: A developmental study with a multistaged approach. We derived a first set of knowledge components from literature and subsequently performed semistructured interviews with 9 experts. We refined the set of knowledge components and checked it with the interviewees for final approval.Results: Understanding the test-management pathway, for example, how test results should be used in context of decisions about interventions, is the key knowledge component. The final list includes 26 items on the following topics: health question, test-management pathway, target population, test, test result, interpretation of test results and subsequent management, and impact on people important outcomes. For each item, the required level of knowledge is defined. Conclusion: We developed a list of knowledge components required for guideline panels to formulate recommendations on healthcare related testing. The list could be used to design specific training programs for guideline panel members when developing recommendations about tests and testing strategies in healthcare.</p

Topological and geometrical restrictions, free-boundary problems and self-gravitating fluids

Let (P1) be certain elliptic free-boundary problem on a Riemannian manifold (M,g). In this paper we study the restrictions on the topology and geometry of the fibres (the level sets) of the solutions f to (P1). We give a technique based on certain remarkable property of the fibres (the analytic representation property) for going from the initial PDE to a global analytical characterization of the fibres (the equilibrium partition condition). We study this analytical characterization and obtain several topological and geometrical properties that the fibres of the solutions must possess, depending on the topology of M and the metric tensor g. We apply these results to the classical problem in physics of classifying the equilibrium shapes of both Newtonian and relativistic static self-gravitating fluids. We also suggest a relationship with the isometries of a Riemannian manifold.Comment: 36 pages. In this new version the analytic representation hypothesis is proved. Please address all correspondence to D. Peralta-Sala

The Large Magellanic Cloud and the Distance Scale

The Magellanic Clouds, especially the Large Magellanic Cloud, are places where multiple distance indicators can be compared with each other in a straight-forward manner at considerable precision. We here review the distances derived from Cepheids, Red Variables, RR Lyraes, Red Clump Stars and Eclipsing Binaries, and show that the results from these distance indicators generally agree to within their errors, and the distance modulus to the Large Magellanic Cloud appears to be defined to 3% with a mean value of 18.48 mag, corresponding to 49.7 Kpc. The utility of the Magellanic Clouds in constructing and testing the distance scale will remain as we move into the era of Gaia.Comment: 23 pages, accepted for publication in Astrophysics and Space Science. From a presentation at the conference The Fundamental Cosmic Distance Scale: State of the Art and the Gaia Perspective, Naples, May 201