Primary osteoblast-like cells from patients with end-stage kidney disease reflect gene expression, proliferation, and mineralization characteristics ex vivo.

Osteocytes regulate bone turnover and mineralization in chronic kidney disease. As osteocytes are derived from osteoblasts, alterations in osteoblast function may regulate osteoblast maturation, osteocytic transition, bone turnover, and skeletal mineralization. Thus, primary osteoblast-like cells were cultured from bone chips obtained from 24 pediatric ESKD patients. RNA expression in cultured cells was compared with RNA expression in cells from healthy individuals, to RNA expression in the bone core itself, and to parameters of bone histomorphometry. Proliferation and mineralization rates of patient cells were compared with rates in healthy control cells. Associations were observed between bone osteoid accumulation, as assessed by bone histomorphometry, and bone core RNA expression of osterix, matrix gla protein, parathyroid hormone receptor 1, and RANKL. Gene expression of osteoblast markers was increased in cells from ESKD patients and signaling genes including Cyp24A1, Cyp27B1, VDR, and NHERF1 correlated between cells and bone cores. Cells from patients with high turnover renal osteodystrophy proliferated more rapidly and mineralized more slowly than did cells from healthy controls. Thus, primary osteoblasts obtained from patients with ESKD retain changes in gene expression ex vivo that are also observed in bone core specimens. Evaluation of these cells in vitro may provide further insights into the abnormal bone biology that persists, despite current therapies, in patients with ESKD

Simulating the impact of tax incentives using a type choice model for lease cars

Tax incentives for hybrid and electric cars are one of the possible policy instruments to reduce the CO2 emissions of cars. This paper looks at the impacts of this policy in the context of The Netherlands, where up to 2016 substantial tax incentives were provided to fuel efficient lease cars, especially for hybrid and electric lease cars. For this analysis this paper uses a new model of vehicle type choice. Existing models for the choice among car type alternatives either exclude electric and hybrid cars or are based on stated preference data. In both cases, the models usually focus on privately-owned cars. The car type choice model for lease cars, that is used in this paper, includes electric and hybrid alternatives and is estimated on revealed preference data from lease car users in The Netherlands. Simulations with this model show that the tax incentives provided over the period 2011–2016 have led to a reduction in CO2 emissions of lease cars, but also to an increase in the share of diesel cars and local air pollution

Reconstructing the molecular life history of gliomas.

At the time of their clinical manifestation, the heterogeneous group of adult and pediatric gliomas carries a wide range of diverse somatic genomic alterations, ranging from somatic single-nucleotide variants to structural chromosomal rearrangements. Somatic abnormalities may have functional consequences, such as a decrease, increase or change in mRNA transcripts, and cells pay a penalty for maintaining them. These abnormalities, therefore, must provide cells with a competitive advantage to become engrained into the glioma genome. Here, we propose a model of gliomagenesis consisting of the following five consecutive phases that glioma cells have traversed prior to clinical manifestation: (I) initial growth; (II) oncogene-induced senescence; (III) stressed growth; (IV) replicative senescence/crisis; (V) immortal growth. We have integrated the findings from a large number of studies in biology and (neuro)oncology and relate somatic alterations and other results discussed in these papers to each of these five phases. Understanding the story that each glioma tells at presentation may ultimately facilitate the design of novel, more effective therapeutic approaches. Acta Neuropathol 2018 May; 135(5):649-670

Optimal, scalable forward models for computing gravity anomalies

We describe three approaches for computing a gravity signal from a density anomaly. The first approach consists of the classical "summation" technique, whilst the remaining two methods solve the Poisson problem for the gravitational potential using either a Finite Element (FE) discretization employing a multilevel preconditioner, or a Green's function evaluated with the Fast Multipole Method (FMM). The methods utilizing the PDE formulation described here differ from previously published approaches used in gravity modeling in that they are optimal, implying that both the memory and computational time required scale linearly with respect to the number of unknowns in the potential field. Additionally, all of the implementations presented here are developed such that the computations can be performed in a massively parallel, distributed memory computing environment. Through numerical experiments, we compare the methods on the basis of their discretization error, CPU time and parallel scalability. We demonstrate the parallel scalability of all these techniques by running forward models with up to $10^8$ voxels on 1000's of cores.Comment: 38 pages, 13 figures; accepted by Geophysical Journal Internationa

Alternative reproductive tactics, sperm mobility and oxidative stress in Carollia perspicillata (Seba's short-tailed bat)

In social systems with alternative reproductive tactics, sneakers face a higher level of sperm competition than harem males and hence are predicted to allocate more resources to ejaculates. Antioxidants can protect sperm against oxidative stress, and thus, their allocation to the ejaculate may depend on mating tactic. In this study on the frugivorous bat Carollia perspicillata, we assessed, for harem and sneaker males, four spermmobility traits, blood and ejaculatemarkers of the redox balance and the ejaculate to blood ratios of the redox markers. Under higher sperm competition, sneaker males should allocate proportionally more antioxidant resources to the protection of sperm than harem males. In contrast, harem males should favour pre-copulatory functions, which comprise the protection of blood. We found significantly higher sperm velocity and sperm survival in sneakers. There was no correlation between spermmobility and spermenzymatic antioxidant activity or ejaculate levels of lipid peroxidation (oxidative damage). Ejaculate levels of lipid peroxidation and sperm survival showed a significantly positive correlation, which could be attributed to the role of reactive oxygen species for sperm capacitation. Harem and sneaker males showed similar levels of redox balance markers in ejaculate and blood. However, harem males showed a higher ratio of oxidized over reduced glutathione in blood, which may indicate higher cellular stress due to higher metabolism. Overall, our findings suggest that sneakers of C. perspicillata compensate for a higher level of sperm competition by higher sperm mobility. Significance statement In social systems with alternative reproductive tactics, sneakers face higher level of sperm competition than harem males and hence are predicted to allocate more resources to ejaculates. Antioxidants can protect sperm against oxidative stress, and thus, their allocation to the ejaculate may depend on mating tactic. In this study on the frugivorous bat Carollia perspicillata, we found sperm swimming significantly faster and longer in sneaker males compared to harem males. However, traits other than the investigated antioxidant may favour higher sperm mobility. Measured redox pattern in blood of harem males may indicate higher cellular stress due to higher metabolism. Our results provide support to the current sperm competition models at the intraspecific level, which is still debated for internal fertilizers. This study contributes to better understanding the trade-offs and adaptations resulting from alternative reproductive tactics in mammals

Proteomic systems evaluation of the molecular validity of preclinical psychosis models compared to schizophrenia brain pathology.

Pharmacological and genetic rodent models of schizophrenia play an important role in the drug discovery pipeline, but quantifying the molecular similarity of such models with the underlying human pathophysiology has proved difficult. We developed a novel systems biology methodology for the direct comparison of anterior prefrontal cortex tissue from four established glutamatergic rodent models and schizophrenia patients, enabling the evaluation of which model displays the greatest similarity to schizophrenia across different pathophysiological characteristics of the disease. Liquid chromatography coupled tandem mass spectrometry (LC-MSE) proteomic profiling was applied comparing healthy and "disease state" in human post-mortem samples and rodent brain tissue samples derived from models based on acute and chronic phencyclidine (PCP) treatment, ketamine treatment or NMDA receptor knockdown. Protein-protein interaction networks were constructed from significant abundance changes and enrichment analyses enabled the identification of five functional domains of the disease such as "development and differentiation", which were represented across all four rodent models and were thus subsequently used for cross-species comparison. Kernel-based machine learning techniques quantified that the chronic PCP model represented schizophrenia brain changes most closely for four of these functional domains. This is the first study aiming to quantify which rodent model recapitulates the neuropathological features of schizophrenia most closely, providing an indication of face validity as well as potential guidance in the refinement of construct and predictive validity. The methodology and findings presented here support recent efforts to overcome translational hurdles of preclinical psychiatric research by associating functional dimensions of behaviour with distinct biological processes.This research was supported by the Stanley Medical Research Institute (SMRI) (R6123) and the NEWMEDS Innovative Medicines Initiative (FP7/2007-2013).This is the author accepted manuscript. The final version is available from Elsevier via https://doi.org/10.1016/j.schres.2016.06.01

Nuclear structure studies with the 7Li(e,e'p) reaction

Experimental momentum distributions for the transitions to the ground state and first excited state of 6He have been measured via the reaction 7Li(e,e'p)6He, in the missing momentum range from -70 to 260 MeV/c. They are compared to theoretical distributions calculated with mean-field wave functions and with variational Monte Carlo (VMC) wave functions which include strong state-dependent correlations in both 7Li and 6He. These VMC calculations provide a parameter-free prediction of the momentum distribution that reproduces the measured data, including its normalization. The deduced summed spectroscopic factor for the two transitions is 0.58 +/- 0.05, in perfect agreement with the VMC value of 0.60. This is the first successful comparison of experiment and ab initio theory for spectroscopic factors in p-shell nuclei.Comment: 4 pages, 3 figure

Tips for implementing multigrid methods on domains containing holes

As part of our development of a computer code to perform 3D `constrained evolution' of Einstein's equations in 3+1 form, we discuss issues regarding the efficient solution of elliptic equations on domains containing holes (i.e., excised regions), via the multigrid method. We consider as a test case the Poisson equation with a nonlinear term added, as a means of illustrating the principles involved, and move to a "real world" 3-dimensional problem which is the solution of the conformally flat Hamiltonian constraint with Dirichlet and Robin boundary conditions. Using our vertex-centered multigrid code, we demonstrate globally second-order-accurate solutions of elliptic equations over domains containing holes, in two and three spatial dimensions. Keys to the success of this method are the choice of the restriction operator near the holes and definition of the location of the inner boundary. In some cases (e.g. two holes in two dimensions), more and more smoothing may be required as the mesh spacing decreases to zero; however for the resolutions currently of interest to many numerical relativists, it is feasible to maintain second order convergence by concentrating smoothing (spatially) where it is needed most. This paper, and our publicly available source code, are intended to serve as semi-pedagogical guides for those who may wish to implement similar schemes.Comment: 18 pages, 11 figures, LaTeX. Added clarifications and references re. scope of paper, mathematical foundations, relevance of work. Accepted for publication in Classical & Quantum Gravit