Regulation of mitochondrial biogenesis in erythropoiesis by mTORC1-mediated protein translation.

Advances in genomic profiling present new challenges of explaining how changes in DNA and RNA are translated into proteins linking genotype to phenotype. Here we compare the genome-scale proteomic and transcriptomic changes in human primary haematopoietic stem/progenitor cells and erythroid progenitors, and uncover pathways related to mitochondrial biogenesis enhanced through post-transcriptional regulation. Mitochondrial factors including TFAM and PHB2 are selectively regulated through protein translation during erythroid specification. Depletion of TFAM in erythroid cells alters intracellular metabolism, leading to elevated histone acetylation, deregulated gene expression, and defective mitochondria and erythropoiesis. Mechanistically, mTORC1 signalling is enhanced to promote translation of mitochondria-associated transcripts through TOP-like motifs. Genetic and pharmacological perturbation of mitochondria or mTORC1 specifically impairs erythropoiesis in vitro and in vivo. Our studies support a mechanism for post-transcriptional control of erythroid mitochondria and may have direct relevance to haematologic defects associated with mitochondrial diseases and ageing

Spatial correlations between MRI-derived wall shear stress and vessel wall thickness in the carotid bifurcation

BACKGROUND: To explore the possibility of creating three-dimensional (3D) estimation models for patient-specific wall thickness (WT) maps using patient-specific and cohort-averaged WT, wall shear stress (WSS), and vessel diameter maps in asymptomatic atherosclerotic carotid bifurcations. METHODS: Twenty subjects (aged 75 ± 6 years [mean ± standard deviation], eight women) underwent a 1.5-T MRI examination. Non-gated 3D phase-contrast gradient-echo images and proton density-weighted echo-planar images were retrospectively assessed for WSS, diameter estimation, and WT measurements. Spearman's ρ and scatter plots were used to determine correlations between individual WT, WSS, and diameter maps. A bootstrapping technique was used to determine correlations between 3D cohort-averaged WT, WSS, and diameter maps. Linear regression between the cohort-averaged WT, WSS, and diameter maps was used to predict individual 3D WT. RESULTS: Spearman's ρ averaged over the subjects was - 0.24 ± 0.18 (p < 0.001) and 0.07 ± 0.28 (p = 0.413) for WT versus WSS and for WT versus diameter relations, respectively. Cohort-averaged ρ, averaged over 1000 bootstraps, was - 0.56 (95% confidence interval [- 0.74,- 0.38]) for WT versus WSS and 0.23 (95% confidence interval [- 0.06, 0.52]) for WT versus diameter. Scatter plots did not reveal relationships between individual WT and WSS or between WT and diameter data. Linear relationships between these parameters became apparent after averaging over the cohort. Spearman's ρ between the original and predicted WT maps was 0.21 ± 0.22 (p < 0.001). CONCLUSIONS: With a combination of bootstrapping and cohort-averaging methods, 3D WT maps can be predicted from the individual 3D WSS and diameter maps. The methodology may help to elucidate pathological processes involving WSS in carotid atherosclerosis

Iron homeostasis and oxidative stress in idiopathic pulmonary alveolar proteinosis: a case-control study

<p>Abstract</p> <p>Background</p> <p>Lung injury caused by both inhaled dusts and infectious agents depends on increased availability of iron and metal-catalyzed oxidative stress. Because inhaled particles, such as silica, and certain infections can cause secondary pulmonary alveolar proteinosis (PAP), we tested the hypothesis that idiopathic PAP is associated with an altered iron homeostasis in the human lung.</p> <p>Methods</p> <p>Healthy volunteers (n = 20) and patients with idiopathic PAP (n = 20) underwent bronchoalveolar lavage and measurements were made of total protein, iron, tranferrin, transferrin receptor, lactoferrin, and ferritin. Histochemical staining for iron and ferritin was done in the cell pellets from control subjects and PAP patients, and in lung specimens of patients without cardiopulmonary disease and with PAP. Lavage concentrations of urate, glutathione, and ascorbate were also measured as indices of oxidative stress.</p> <p>Results</p> <p>Lavage concentrations of iron, transferrin, transferrin receptor, lactoferrin, and ferritin were significantly elevated in PAP patients relative to healthy volunteers. The cells of PAP patients had accumulated significant iron and ferritin, as well as considerable amounts of extracellular ferritin. Immunohistochemistry for ferritin in lung tissue revealed comparable amounts of this metal-storage protein in the lower respiratory tract of PAP patients both intracellularly and extracellularly. Lavage concentrations of ascorbate, glutathione, and urate were significantly lower in the lavage fluid of the PAP patients.</p> <p>Conclusion</p> <p>Iron homeostasis is altered in the lungs of patients with idiopathic PAP, as large amounts of catalytically-active iron and low molecular weight anti-oxidant depletion are present. These findings suggest a metal-catalyzed oxidative stress in the maintenance of this disease.</p

Pilot performance of a dedicated prostate PET suitable for diagnosis and biopsy guidance

[EN] Background: Prostate cancer (PCa) represents one of the most common types of cancers facing the male population. Nowadays, to confirm PCa, systematic or multiparametric MRI-targeted transrectal or transperineal biopsies of the prostate are required. However, due to the lack of an accurate imaging technique capable to precisely locate cancerous cells in the prostate, ultrasound biopsies sample random parts of the prostate and, therefore, it is possible to miss regions where those cancerous cells are present. In spite of the improvement with multiparametric MRI, the low reproducibility of its reading undermines the specificity of the method. Recent development of prostatespecific radiotracers has grown the interest on using positron emission tomography (PET) scanners for this purpose, but technological improvements are still required (current scanners have resolutions in the range of 4¿5 mm). Results: The main goal of this work is to improve state-of-the-art PCa imaging and diagnosis. We have focused our efforts on the design of a novel prostate-dedicated PET scanner, named ProsPET. This system has small scanner dimensions defined by a ring of just 41 cm inner diameter. In this work, we report the design, implementation, and evaluation (both through simulations and real data) of the ProsPET scanner. We have been able to achieve < 2 mm resolution in reconstructed images and high sensitivity. In addition, we have included a comparison with the Philips Gemini-TF scanner, which is used for routine imaging of PCa patients. The ProsPET exhibits better contrast, especially for rod sizes as small as 4.5 mm in diameter. Finally, we also show the first reconstructed image of a PCa patient acquired with the ProsPET. Conclusions: We have designed and built a prostate specific PET system, with a small footprint and improved spatial resolution when compared to conventional whole-body PET scanners. The gamma ray impact within each detector block includes accurate DOI determination, correcting for the parallax error. The potential role of combined organdedicated prostate-specific membrane antigen (PSMA) PET and ultrasound devices, as a prebiopsy diagnostic tool, could be used to guide sampling of the most aggressive sites in the prostate.The work presented in this article has been partially funded by a research grant from the regional government of the Comunitat Valenciana (Spain), co-funded by the European Union ERDF funds (European Regional Development Fund) of the Comunitat Valenciana 2014-2020, with reference IDIFEDER/2018/032 (High-Performance Algorithms for the Modelling, Simulation and early Detection of diseases in Personalized Medicine). This project has also received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement No 695536). It has also been supported by the EU Grant 603002 under the FP7 program and by the Spanish Ministerio de Economia, Industria y Competitividad under Grant e and through PROSPET (DTS15/00152) funded by the Ministerio de Economia y Competitividad.Cañizares-Ledo, G.; Gonzalez-Montoro, A.; Freire, M.; Lamprou, E.; Barrio, J.; Sánchez Martínez, F.; Benlloch Baviera, JM.... (2020). Pilot performance of a dedicated prostate PET suitable for diagnosis and biopsy guidance. EJNMMI Physics. 7(1):1-17. https://doi.org/10.1186/s40658-020-00305-yS11771GLOBOCAN 2018. http://www.gco.iarc.fr/today/ datasources-methods. Accessed 26 Dec 2019.Ferlay J, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN. Int J Cancer. 2012;2015:136–E359.Rawla P. Epidemiology of prostate cancer. 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MR-guided focused ultrasound: enhancement of intratumoral uptake of [H]-docetaxel in vivo. Phys Med Biol. 2010;55(24):–7399.Osborne JR, et al. Prostate-specific membrane antigen-based imaging. Seminars and Original Investigations: Urologic Oncology; 2012.Gonzalez AJ, et al. Organ-dedicated molecular imaging systems. IEEE Trans. Rad. Plasma Med. Scie. 2018;2:388.Majewski S, Proffitt J. Dedicated mobile high resolution prostate PET imager with an insertable transrectal probe. US Patent. 2010;7:858–944.Weinberg IN, et al. Flexible geometries for hand-held PET and SPECT cameras. IEEE NSS-MIC Conference Record. 2002.Weinberg I. Dedicated apparatus and method for positron emission tomography of the prostate. US Patent. 2006;7:102–34.Gonzalez-Montoro A, et al. Performance study of a large monolithic LYSO PET detector with accurate photon DOI using retroreflector layers. IEEE Trans. Rad. Plasma Med. Scie. 2017;1:229.Gonzalez-Montoro A, et al. Detector block performance based on a monolithic LYSO crystal using a novel signal multiplexing method. Nucl Instrum Meth. 2018;912:372-77.Gonzalez-Montoro A, et al. Performance comparison of large-area SiPM arrays suitable for gamma ray detectors. Biomed Phys Eng Express. 2019;5:045013.Seimetz M, et al. Correction algorithms for signal reduction in insensitive areas of a small gamma camera. J Instrum. 2014;9(05):C05042.Freire M, et al. Calibration of gamma ray impacts in monolithic-based detectors using Voronoi diagrams. In IEEE Transactions on Radiation and Plasma Medical Sciences. 2019. https://doi.org/10.1109/TRPMS.2019.2947716 .Jan S, et al. GATE: a simulation toolkit for PET and SPECT. Phys Med Biol. 2004;49:4543–61.Merlin T, et al. CASToR: a generic data organization and processing code framework for multi-modal and multi-dimensional tomographic reconstruction. Phys Med Biol. 2018;63(18):5505.Jacobs F, et al. A fast algorithm to calculate the exact radiological path through a pixel or voxel space. J Comput Inf Technol. 1998;6(1).Gonzalez-Montoro A, et al. Novel method to measure the intrinsic spatial resolution in PET detectors based on monolithic crystals. Nucl. Instrum. Meth. A. 2019;920:39(9).Vicente E, et al. Normalization in 3D PET: dependence on the activity distribution of the source. IEEE Nuclear Science Symposium Conference Record. 2006:M06–379.Soriano A, et al. Attenuation correction without transmission scan for the MAMMI breast PET. Nucl Instrum Meth A. 2011;648:S75.Yushkevich PA, et al. User-guided 3D active contour segmentation of anatomical structures: significantly improved efficiency and reliability. Neuroimage. 2006;34(3):1116-28.Gonzalez AJ, et al. Initial results of the MINDView PET insert inside the 3T mMR. IEEE Trans Rad Plasma Med Scie. 2019;3:343.Suti S, et al. 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Against quantiles: categorization of continuous variables in epidemiologic research, and its discontents

<p>Abstract</p> <p>Background</p> <p>Quantiles are a staple of epidemiologic research: in contemporary epidemiologic practice, continuous variables are typically categorized into tertiles, quartiles and quintiles as a means to illustrate the relationship between a continuous exposure and a binary outcome.</p> <p>Discussion</p> <p>In this paper we argue that this approach is highly problematic and present several potential alternatives. We also discuss the perceived drawbacks of these newer statistical methods and the possible reasons for their slow adoption by epidemiologists.</p> <p>Summary</p> <p>The use of quantiles is often inadequate for epidemiologic research with continuous variables.</p

Spin and Chirality Effects in Antler-Topology Processes at High Energy e+e−e^+e^- Colliders

We perform a model-independent investigation of spin and chirality correlation effects in the antler-topology processes $e^+e^-\to\mathcal{P}^+\mathcal{P}^-\to (\ell^+ \mathcal{D}^0) (\ell^-\mathcal{\bar{D}}^0)$ at high energy $e^+e^-$ colliders with polarized beams. Generally the production process $e^+e^-\to\mathcal{P}^+\mathcal{P}^-$ can occur not only through the $s$-channel exchange of vector bosons, $\mathcal{V}^0$, including the neutral Standard Model (SM) gauge bosons, $\gamma$ and $Z$, but also through the $s$- and $t$-channel exchanges of new neutral states, $\mathcal{S}^0$ and $\mathcal{T}^0$, and the $u$-channel exchange of new doubly-charged states, $\mathcal{U}^{--}$. The general set of (non-chiral) three-point couplings of the new particles and leptons allowed in a renormalizable quantum field theory is considered. The general spin and chirality analysis is based on the threshold behavior of the excitation curves for $\mathcal{P}^+\mathcal{P}^-$ pair production in $e^+e^-$ collisions with longitudinal and transverse polarized beams, the angular distributions in the production process and also the production-decay angular correlations. In the first step, we present the observables in the helicity formalism. Subsequently, we show how a set of observables can be designed for determining the spins and chiral structures of the new particles without any model assumptions. Finally, taking into account a typical set of approximately chiral invariant scenarios, we demonstrate how the spin and chirality effects can be probed experimentally at a high energy $e^+e^-$ collider.Comment: 50 pages, 14 figures, 6 tables, matches version published in EPJ

Minimal flavour violation extensions of the seesaw

We analyze the most natural formulations of the minimal lepton flavour violation hypothesis compatible with a type-I seesaw structure with three heavy singlet neutrinos N, and satisfying the requirement of being predictive, in the sense that all LFV effects can be expressed in terms of low energy observables. We find a new interesting realization based on the flavour group $SU(3)_e\times SU(3)_{\ell+N}$ (being $e$ and $\ell$ respectively the SU(2) singlet and doublet leptons). An intriguing feature of this realization is that, in the normal hierarchy scenario for neutrino masses, it allows for sizeable enhancements of $\mu \to e$ transitions with respect to LFV processes involving the $\tau$ lepton. We also discuss how the symmetries of the type-I seesaw allow for a strong suppression of the N mass scale with respect to the scale of lepton number breaking, without implying a similar suppression for possible mechanisms of N productionComment: 14 pages, 6 figure

Exploring novel correlations in trilepton channels at the LHC for the minimal supersymmetric inverse seesaw model

We investigate signatures of the minimal supersymmetric inverse seesaw model at the large hadron collider (LHC) with three isolated leptons and large missing energy (3\ell + \mET or 2\ell + 1\tau + \mET, with \ell=e,\mu) in the final state. This signal has its origin in the decay of chargino-neutralino (\chpm1\ntrl2) pair, produced in pp collisions. The two body decays of the lighter chargino into a charged lepton and a singlet sneutrino has a characteristic decay pattern which is correlated with the observed large atmospheric neutrino mixing angle. This correlation is potentially observable at the LHC by looking at the ratios of cross sections of the trilepton + \mET channels in certain flavour specific modes. We show that even after considering possible leading standard model backgrounds these final states can lead to reasonable discovery significance at the LHC with both 7 TeV and 14 TeV center-of-mass energy.Comment: 28 pages, 9 .eps figures. 3 new figures and discussions on LHC observables added, minor modifications in text and in the abstract, 23 new references added, matches with the published version in JHE

Goldstone Bosons in Effective Theories with Spontaneously Broken Flavour Symmetry

The Flavour Symmetry of the Standard Model (SM) gauge sector is broken by the fermion Yukawa couplings. Promoting the Yukawa matrices to scalar spurion fields, one can break the flavour symmetry spontaneously by giving appropriate vacuum expectation values (VEVs) to the spurion fields, and one encounters Goldstone modes for every broken flavour symmetry generator. In this paper, we point out various aspects related to the possible dynamical interpretation of the Goldstone bosons: (i) In an effective-theory framework with local flavour symmetry, the Goldstone fields represent the longitudinal modes for massive gauge bosons. The spectrum of the latter follows the sequence of flavour-symmetry breaking related to the hierarchies in Yukawa couplings and flavour mixing angles. (ii) Gauge anomalies can be consistently treated by adding higher-dimensional operators. (iii) Leaving the U(1) factors of the flavour symmetry group as global symmetries, the respective Goldstone modes behave as axions which can be used to resolve the strong CP problem by a modified Peccei-Quinn mechanism. (iv) The dynamical picture of flavour symmetry breaking implies new sources of flavour-changing neutral currents, which arise from integrating out heavy scalar spurion fields and heavy gauge bosons. The coefficients of the effective operators follow the minimal-flavour violation principle.Comment: 27 pages, abstract and introduction extended, more detailed discussion of heavy gauge boson spectrum and auxiliary heavy fermions, outline restructured. Matches version to be published in JHE

MI-GWAS: a SAS platform for the analysis of inherited and maternal genetic effects in genome-wide association studies using log-linear models

<p>Abstract</p> <p>Background</p> <p>Several platforms for the analysis of genome-wide association data are available. However, these platforms focus on the evaluation of the genotype inherited by affected (i.e. case) individuals, whereas for some conditions (e.g. birth defects) the genotype of the mothers of affected individuals may also contribute to risk. For such conditions, it is critical to evaluate associations with both the maternal and the inherited (i.e. case) genotype. When genotype data are available for case-parent triads, a likelihood-based approach using log-linear modeling can be used to assess both the maternal and inherited genotypes. However, available software packages for log-linear analyses are not well suited to the analysis of typical genome-wide association data (e.g. including missing data).</p> <p>Results</p> <p>An integrated platform, Maternal and Inherited Analyses for Genome-wide Association Studies <b>(</b>MI-GWAS) for log-linear analyses of maternal and inherited genetic effects in large, genome-wide datasets, is described. MI-GWAS uses SAS and LEM software in combination to appropriately format data, perform the log-linear analyses and summarize the results. This platform was evaluated using existing genome-wide data and was shown to perform accurately and relatively efficiently.</p> <p>Conclusions</p> <p>The MI-GWAS platform provides a valuable tool for the analysis of association of a phenotype or condition with maternal and inherited genotypes using genome-wide data from case-parent triads. The source code for this platform is freely available at <url>http://www.sph.uth.tmc.edu/sbrr/mi-gwas.htm</url>.</p