Hamiltonian Noether theorem for gauge systems and two time physics

The Noether theorem for Hamiltonian constrained systems is revisited. In particular, our review presents a novel method to show that the gauge transformations are generated by the conserved quantities associated with the first class constraints. We apply our results to the relativistic point particle, to the Friedberg et al. model and, with special emphasis, to two time physics.Comment: 20 pages, Latex, references added, the "massless" sense of (87) is clarifie

Snail blocks the cell cycle and confers resistance to cell death

The Snail zinc-finger transcription factors trigger epithelial-mesenchymal transitions (EMTs), endowing epithelial cells with migratory and invasive properties during both embryonic development and tumor progression. During EMT, Snail provokes the loss of epithelial markers, as well as changes in cell shape and the expression of mesenchymal markers. Here, we show that in addition to inducing dramatic phenotypic alterations, Snail attenuates the cell cycle and confers resistance to cell death induced by the withdrawal of survival factors and by pro-apoptotic signals. Hence, Snail favors changes in cell shape versus cell division, indicating that with respect to oncogenesis, although a deregulation/increase in proliferation is crucial for tumor formation and growth, this may not be so for tumor malignization. Finally, the resistance to cell death conferred by Snail provides a selective advantage to embryonic cells to migrate and colonize distant territories, and to malignant cells to separate from the primary tumor, invade, and form metastasis

Specific gene correction of the AGXT gene and direct cell reprogramming for the treatment of Primary Hyperoxaluria Type 1

P428 Primary Hyperoxaluria Type 1 (PH1) is an inherited rare metabolic liver disease caused by the deficiency in the alanine: glyoxylate aminotransferase enzyme (AGXT), involved in the glyoxylate metabolism. The only potentially curative treatment is organ transplantation. Thus, the development of new therapeutic approaches for the treatment of these patients appears as a priority.We propose the combination of site-specific gene correction and direct cell reprogramming for the generation of autologous phenotypically healthy induced hepatocytes (iHeps) from skin-derived fibroblast of PH1 patients. For the correction of AGXT mutations, we have designed specific gene editing tools to address gene correction by two different strategies, assisted by CRISPR/Cas9 system. Accurate specific point mutation correction (c.853T-C) has been achieved by homologydirected repair (HDR) with ssODN harbouring wild-type sequence. In the second strategy, an enhanced version ofAGXTcDNAhas been inserted near the transcription start codon of the endogenous gene, constituting an almost universal correction strategy for PH1 mutations. Direct reprogramming of fibroblasts has been conducted by overexpression of hepatic transcription factors and in vitro culture in defined media. In vitro characterization of healthy induced hepatocytes (iHeps) has demonstrated hepatic function of the reprogrammed cells. PH1 patient fibroblasts and , ,

High optimization process for increasing the attenuation properties of acoustic metamaterials by means of the creation of defects

Copyright (2008) American Institute of Physics. This article may be downloaded for personal use only. Any other use requires prior permission of the author and the American Institute of Physics along with the following message: The following article appeared in “Romero García, V.; Sánchez Pérez, JV.; García-Raffi, LM.; Herrero Durá, JM.; S. Garcia-Nieto; Blasco Ferragud, FX. (2008). High optimization process for increasing the attenuation properties of acoustic metamaterials by means of the creation of defects. Applied Physics Letters. 93:2235021-2235023” and may be found at http://dx.doi.org/10.1063/1.3040317. Authors own version of final article on e-print serversAn improvement in the attenuation capabilities of acoustic metamaterials by means of the creation of defects is considered here as a multiobjective optimization problem. From this point of view, it is possible to define the optimum strategy in the creation of defects to achieve an important increase in acoustic attenuation in a predetermined range of frequencies. A powerful multiobjective optimization algorithm called evMOGA has been used to solve this problem. The study has been restricted to the case of a two-dimensional sonic crystal formed by rigid cylinders in air, the defects being vacancies in the initial structure.This work was partially supported by MEC (Spanish Government) and FEDER funds: Project Nos. 419DPI2005-07835 and MAT2006-03097 and Generalitat Valenciana Project Nos. GV06/026 and GV/2007/191.Romero García, V.; Sánchez Pérez, JV.; García-Raffi, LM.; Herrero Durá, JM.; García Nieto, S.; Blasco Ferragud, FX. (2008). High optimization process for increasing the attenuation properties of acoustic metamaterials by means of the creation of defects. Applied Physics Letters. 93(22):2235021-2235023. https://doi.org/10.1063/1.3040317S223502122350239322Fang, N., Xi, D., Xu, J., Ambati, M., Srituravanich, W., Sun, C., & Zhang, X. (2006). Ultrasonic metamaterials with negative modulus. Nature Materials, 5(6), 452-456. doi:10.1038/nmat1644Torrent, D., & Sánchez-Dehesa, J. (2008). Anisotropic mass density by two-dimensional acoustic metamaterials. New Journal of Physics, 10(2), 023004. doi:10.1088/1367-2630/10/2/023004Sánchez-Pérez, J. V., Caballero, D., Mártinez-Sala, R., Rubio, C., Sánchez-Dehesa, J., Meseguer, F., … Gálvez, F. (1998). Sound Attenuation by a Two-Dimensional Array of Rigid Cylinders. Physical Review Letters, 80(24), 5325-5328. doi:10.1103/physrevlett.80.5325Fokin, V., Ambati, M., Sun, C., & Zhang, X. (2007). Method for retrieving effective properties of locally resonant acoustic metamaterials. Physical Review B, 76(14). doi:10.1103/physrevb.76.144302Sanchez-Perez, J. V., Rubio, C., Martinez-Sala, R., Sanchez-Grandia, R., & Gomez, V. (2002). Acoustic barriers based on periodic arrays of scatterers. Applied Physics Letters, 81(27), 5240-5242. doi:10.1063/1.1533112Torrent, D., & Sánchez-Dehesa, J. (2007). Acoustic metamaterials for new two-dimensional sonic devices. New Journal of Physics, 9(9), 323-323. doi:10.1088/1367-2630/9/9/323Romero-García, V., Fuster, E., García-Raffi, L. M., Sánchez-Pérez, E. A., Sopena, M., Llinares, J., & Sánchez-Pérez, J. V. (2006). Band gap creation using quasiordered structures based on sonic crystals. Applied Physics Letters, 88(17), 174104. doi:10.1063/1.2198012Herrero, J. M., Blasco, X., Martínez, M., Ramos, C., & Sanchis, J. (2007). Non-linear robust identification of a greenhouse model using multi-objective evolutionary algorithms. Biosystems Engineering, 98(3), 335-346. doi:10.1016/j.biosystemseng.2007.06.004Kafesaki, M., & Economou, E. N. (1999). Multiple-scattering theory for three-dimensional periodic acoustic composites. Physical Review B, 60(17), 11993-12001. doi:10.1103/physrevb.60.11993Ehrgott, M., & Tenfelde-Podehl, D. (2003). Computation of ideal and Nadir values and implications for their use in MCDM methods. European Journal of Operational Research, 151(1), 119-139. doi:10.1016/s0377-2217(02)00595-7Coello Coello, C. A., Van Veldhuizen, D. A., & Lamont, G. B. (2002). Evolutionary Algorithms for Solving Multi-Objective Problems. Genetic Algorithms and Evolutionary Computation. doi:10.1007/978-1-4757-5184-

Hole distribution in phononic crystals: design and optimization

An exhaustive study has been made into the potential improvement in attenuation and focusing of phononic crystal arrays resulting from the deliberate creation of vacancies. Use is made of a stochastic search algorithm based on evolutionary algorithms called the epsilon variable multi-objective genetic algorithm which, in conjunction with the application of multiple scattering theory, enables the design of devices for effectively controlling sound waves. Several parameters are analyzed, including the symmetries used in the distribution of holes and the optimum number of holes. The validity and utility of the general rules obtained have been confirmed experimentally.This work was partially supported by MEC (Spanish Government) and FEDER funds: Project Nos. 419DPI2005-07835, and MAT2006-03097 and Generalitat Valenciana Project Nos. GV06/026 and 420 GV/2007/191. The authors would like to thank John Rawlins (associate member of the Institute of Translation and Interpreting (No. 9743) of UK, and "Certified PRO" of ProZ according to the EN 15038) for his help with the use of English.Romero García, V.; Sánchez Pérez, JV.; García Raffi, LM.; Herrero Durá, JM.; García Nieto, S.; Blasco, X. (2009). Hole distribution in phononic crystals: design and optimization. Journal of the Acoustical Society of America. 125(6):3774-3783. https://doi.org/10.1121/1.3126948S37743783125

Clinical and ultrasound thyroid nodule characteristics and their association with cytological and histopathological outcomes: A retrospective multicenter study in high-resolution thyroid nodule clinics

Introduction: Thyroid nodules are a common finding. A high-resolution thyroid nodule clinic (HR-TNC) condenses all tests required for the evaluation of thyroid nodules into a single appointment. We aimed to evaluate the clinical outcomes at HR-TNCs. Design and Methods: A retrospective cross-sectional multicenter study including data from four HR-TNCs in Spain. We evaluated fine-needle aspiration (FNA) indications and the association between clinical and ultrasound characteristics with cytological and histopathological outcomes. Results: A total of 2809 thyroid nodules were included; FNA was performed in 82.1%. Thyroid nodules that underwent FNA were more likely larger, isoechoic, with microcalcifications, and in younger subjects. The rate of nondiagnostic FNA was 4.3%. A solid component, irregular margins or microcalcifications, significantly increased the odds of Bethesda IV-V-VI (vs. Bethesda II). Irregular margins and a solid component were independently associated with increased odds of malignancy. Thyroid nodules <20 mm and ≥20–<40 mm had a 6.5-fold and 3.3-fold increased risk for malignancy respectively in comparison with those ≥40 mm. Conclusion: In this large multicenter study, we found that the presence of a solid component and irregular margins are factors independently related to malignancy in thyroid nodules. Since nodule size ≥40 mm was associated with the lowest odds of malignancy, this cut-off should not be a factor leading to indicate thyroid surgery. HR-TNCs were associated with a low rate of nondiagnostic FNA

Heterogeneous Infectivity and Pathogenesis of SARS-CoV-2 Variants Beta, Delta and Omicron in Transgenic K18-hACE2 and Wildtype Mice

The emerging SARS-CoV-2 variants of concern (VOCs) may display enhanced transmissibility, more severity and/or immune evasion; however, the pathogenesis of these new VOCs in experimental SARS-CoV-2 models or the potential infection of other animal species is not completely understood. Here we infected K18-hACE2 transgenic mice with B.1, B.1.351/Beta, B.1.617.2/Delta and BA.1.1/Omicron isolates and demonstrated heterogeneous infectivity and pathogenesis. B.1.351/Beta variant was the most pathogenic, while BA.1.1/Omicron led to lower viral RNA in the absence of major visible clinical signs. In parallel, we infected wildtype (WT) mice and confirmed that, contrary to B.1 and B.1.617.2/Delta, B.1.351/Beta and BA.1.1/Omicron can infect them. Infection in WT mice coursed without major clinical signs and viral RNA was transient and undetectable in the lungs by day 7 post-infection. In silico modeling supported these findings by predicting B.1.351/Beta receptor binding domain (RBD) mutations result in an increased affinity for both human and murine ACE2 receptors, while BA.1/Omicron RBD mutations only show increased affinity for murine ACE2

The Interplay of Mitochondrial Oxidative Stress and Endoplasmic Reticulum Stress in Cardiovascular Fibrosis in Obese Rats

We have evaluated the role of mitochondrial oxidative stress and its association with endoplasmic reticulum (ER) stress activation in the progression of obesity-related cardiovascular fibrosis. MitoQ (200 µM) was orally administered for 7 weeks to male Wistar rats that were fed a high-fat diet (HFD, 35% fat) or a control diet (CT, 3.5% fat). Obese animals presented cardiovascular fibrosis accompanied by increased levels of extracellular matrix proteins and profibrotic mediators. These alterations were associated with ER stress activation characterized by enhanced levels (in heart and aorta vs. CT group, respectively) of immunoglobulin binding protein (BiP; 2.1-and 2.6-fold, respectively), protein disulfide-isomerase A6 (PDIA6; 1.9-fold) and CCAAT-enhancer-binding homologous protein (CHOP; 1.5- and 1.8-fold, respectively). MitoQ treatment was able to prevent (p < 0.05) these modifications at cardiac and aortic levels. MitoQ (5 nM) and the ER stress inhibitor, 4-phenyl butyric acid (4 µM), were able to block the prooxidant and profibrotic effects of angiotensin II (Ang II, 10−6 M) in cardiac and vascular cells. Therefore, the data show a crosstalk between mitochondrial oxidative stress and ER stress activation, which mediates the development of cardiovascular fibrosis in the context of obesity and in which Ang II can play a relevant role

Quince (Cydonia oblonga) in vitro plant root formation through an automated temporary inmersion system, and its acclimation

Artículo científicoQuince (Cydonia oblonga) is a non-traditional fruit tree found in Costa Rica that has therapeutic and nutritional properties; however its slow growth and root formation prevents the production of a homogeneous population when using conventional farming techniques. Hence, the aim of this research project was to generate uniform plant material in a reduced time span using a temporary immersion bioreactor system (RITAS ®). A semisolid rooting MS culture medium supplemented with 0.1 mg L-1 NAA; 0.3 mg L-1 IBA and 3% sucrose (pH 6.5), developed in the Centro de Investigación en Biotecnología (CIB), Instituto Tecnológico de Costa Rica (ITCR), in Cartago, was used as a reference medium. Four different variations in the sucrose concentration (1%, 2%, 3%, and 4%) were performed in liquid medium. Each trial was evaluated with in vitro plants which had been previously exposed to the culture medium of the corresponding treatments, in a stationary mode and for a 15 day long period, and with in vitro plants without any previous treatment (a total of eight treatments). The comparison of the root formation percentages evidenced the clear effect of sucrose concentration used, with the best results obtained when using the 2% sucrose trial with no pre-treatment (73.3%). The in vitro plants were acclimated in cylinders made out of peat, have previously been disinfected with fungicide, and placed in a humidity chamber at a 20.5°C average temperature and a 75,5% relative humidity for the establishment of weekly fertilizing cycles. The acclimation process generated an 80% survival rate, since several seedlings experienced stem strangulation caused by a fungal attack. The conidiophores identified through optical and scanning electron microscopy evidenced the presence of Cladosporium spp., which was controlled with carbendazim and iprodione fungicides

Mitochondrial Oxidative Stress Promotes Cardiac Remodeling in Myocardial Infarction through the Activation of Endoplasmic Reticulum Stress

We have evaluated cardiac function and fibrosis in infarcted male Wistar rats treated with MitoQ (50 mg/kg/day) or vehicle for 4 weeks. A cohort of patients admitted with a first episode of acute MI were also analyzed with cardiac magnetic resonance and T1 mapping during admission and at a 12-month follow-up. Infarcted animals presented cardiac hypertrophy and a reduction in the left ventricular ejection fraction (LVEF) and E- and A-waves (E/A) ratio when compared to controls. Myocardial infarction (MI) rats also showed cardiac fibrosis and endoplasmic reticulum (ER) stress activation. Binding immunoglobulin protein (BiP) levels, a marker of ER stress, were correlated with collagen I levels. MitoQ reduced oxidative stress and prevented all these changes without affecting the infarct size. The LVEF and E/A ratio in patients with MI were 57.6 ± 7.9% and 0.96 ± 0.34, respectively. No major changes in cardiac function, extracellular volume fraction (ECV), or LV mass were observed at follow-up. Interestingly, the myeloperoxidase (MPO) levels were associated with the ECV in basal conditions. BiP staining and collagen content were also higher in cardiac samples from autopsies of patients who had suffered an MI than in those who had died from other causes. These results show the interactions between mitochondrial oxidative stress and ER stress, which can result in the development of diffuse fibrosis in the context of MI