Mucopolysaccharidosis type II: preliminary data on glycosaminoglycan levels and structure in mice at baseline and after 6 weeks treatment with ERT

Mucopolysaccharidosis type II is a lysosomal storage disease due to the deficit of the enzyme iduronate 2-sulfatase (IDS) and to the consequent accumulation of heparan- (HS) and dermatan-sulfate (DS), with multi-organ involvement. In this study we characterized glycosaminoglycan (GAG) levels and structure in the brain and liver of the Ids knock-out mouse model, at 12 weeks of age and after 6 weeks treatment with human IDS (hIDS) enzyme, by using the capillary electrophoresis-laser induced fluorescence (CE-LIF) technique. As expected, Ids-ko mice showed a heavy accumulation of HS, about 15 times higher than wild-type (wt) in the brain and up to 240 times in the liver. The overall HS charge density rose by 1.5 times only in the liver, but the sulfation pattern changed in both organs. We also observed an increased chondroitin-sulfate (CS)+DS levels of about 2 times in the brain and 5 times in the liver, but an increased CS/DS ratio of about 22 times only in the liver. On the contrary, the hyaluronic acid (HA) levels did not change in both organs. We also conducted the same analysis in Ids-ko mice treated with 1 mg/kg of hIDS, once a week. As expected, we observed in the liver a huge reduction of HS (20 times vs untreated mice) and also of CS+DS and CS/DS. Instead, we did not observe a reduction of the different GAGs in the brain, confirming the enzyme inability to cross BBB. In this district a slight increase of CS/DS ratio, CS+DS and HA levels, and an about 40% increase of HS level, vs untreated ko mice, was observed. On the opposite, the overall HS charge density is decreased 2.5X vs untreated ko and wt mice. This preliminary data underline how by using a more sensitive technique of analysis, a clear separation of the GAGs pattern between wt and Ids-ko mice can be observed. This results particularly important for the brain, where application of common biochemical techniques detects very low GAG levels in both animal types, thus limiting the use of GAG analysis as possible biomarker of therapeutic efficacy in the brain district. The application of CE-LIF analysis is therefore proposed for a detailed evaluation of GAG pattern for potential monitoring of therapeutic efficacy

Clustering environment of BL Lac object RGB 1745+398

The BL Lac object RGB 1745+398 lies in an environment that makes it possible to study the cluster around it more deeply than the environments of other BL Lac objects. The cluster centered on the BL Lac works as a strong gravitational lens, forming a large arc around itself. The aim of this paper is to study the environment and characteristics of this object more accurately than the environments of other BL Lac objects have been before.We measured the redshifts of galaxies in the cluster from the absorption lines in their spectra. The velocity dispersion was then obtained from the redshifts. The gravitational lensing was used for measuring the mass at the center of the cluster. The mass of the whole cluster could then be estimated using the softened isothermal sphere mass distribution. Finally, the richness of the cluster was determined by counting the number of galaxies near the BL Lac object and obtaining the galaxy-BL Lac spatial covariance function, $B_{gb}$. The redshifts of nine galaxies in the field were measured to be near the redshift of the BL Lac object, confirming the presence of a cluster. The average redshift of the cluster is 0.268, and the velocity dispersion $(470^{+190}_{-110})$ km s$^{-1}$. The mass of the cluster is M_{500}=(4^{+3}_{-2})\times10^{14} M_{\sun} which implies a rather massive cluster. The richness measurement also suggests that this is a rich cluster: the result for covariance function is $B_{gb}=(600\pm200)$ Mpc$^{1.77}$, which corresponds to Abell richness class 1 and which is consistent with the mass and velocity dispersion of the cluster.Comment: 5 pages, accepted to A&

Early epigenetic downregulation of microRNA-192 expression promotes pancreatic cancer progression

Pancreatic ductal adenocarcinoma (PDAC) is characterized by very early metastasis, suggesting the hypothesis that metastasis-associated changes may occur prior to actual tumor formation. In this study, we identified miR-192 as an epigenetically regulated suppressor gene with predictive value in this disease. miR-192 was downregulated by promoter methylation in both PDAC and chronic pancreatitis, the latter of which is a major risk factor for the development of PDAC. Functional studies in vitro and in vivo in mouse models of PDAC showed that overexpression of miR-192 was sufficient to reduce cell proliferation and invasion. Mechanistic analyses correlated changes in miR-192 promoter methylation and expression with epithelial–mesenchymal transition. Cell proliferation and invasion were linked to altered expression of the miR-192 target gene SERPINE1 that is encoding the protein plasminogen activator inhibitor-1 (PAI-1), an established regulator of these properties in PDAC cells. Notably, our data suggested that invasive capacity was altered even before neoplastic transformation occurred, as triggered by miR-192 downregulation. Overall, our results highlighted a role for miR-192 in explaining the early metastatic behavior of PDAC and suggested its relevance as a target to develop for early diagnostics and therapy. Cancer Res; 76(14); 4149–59. ©2016 AACR

Women’s pelvic floor muscle strength and urinary and anal incontinence after childbirth: a cross-sectional study

Abstract OBJECTIVE To analyse pelvic floor muscle strength (PFMS) and urinary and anal incontinence (UI and AI) in the postpartum period. METHOD Cross-sectional study carried out with women in their first seven months after child birth. Data were collected through interviews, perineometry (Peritron™), and the International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF). RESULTS 128 women participated in the study. The PFMS mean was 33.1 (SD=16.0) cmH2O and the prevalence of UI and AI was 7.8% and 5.5%, respectively. In the multiple analyses, the variables associated with PFMS were type of birth and cohabitation with a partner. Newborn’s weight, previous pregnancy, UI during pregnancy, and sexual activity showed an association with UI after child birth. Only AI prior to pregnancy was associated with AI after childbirth. CONCLUSION Vaginal birth predisposes to the reduction of PFMS, and caesarean section had a protective effect to its reduction. The occurrence of UI during pregnancy is a predictor of UI after childbirth, and women with previous pregnancies and newborns with higher weights are more likely to have UI after childbirth.AI prior to pregnancy is the only risk factor for its occurrence after childbirth. Associations between PFMS and cohabitation with a partner, and between UI and sexual activity do not make possible to conclude that these variables are directly associated

Dynamics of mechanical waves in periodic grapheme nanoribbon assemblies

We simulate the natural frequencies and the acoustic wave propagation characteristics of graphene nanoribbons (GNRs) of the type (8,0) and (0,8) using an equivalent atomistic-continuum FE model previously developed by some of the authors, where the C-C bonds thickness and average equilibrium lengths during the dynamic loading are identified through the minimisation of the system Hamiltonian. A molecular mechanics model based on the UFF potential is used to benchmark the hybrid FE models developed. The acoustic wave dispersion characteristics of the GNRs are simulated using a Floquet-based wave technique used to predict the pass-stop bands of periodic mechanical structures. We show that the thickness and equilibrium lengths do depend on the specific vibration and dispersion mode considered, and that they are in general different from the classical constant values used in open literature (0.34 nm for thickness and 0.142 nm for equilibrium length). We also show the dependence of the wave dispersion characteristics versus the aspect ratio and edge configurations of the nanoribbons, with widening band-gaps that depend on the chirality of the configurations. The thickness, average equilibrium length and edge type have to be taken into account when nanoribbons are used to design nano-oscillators and novel types of mass sensors based on periodic arrangements of nanostructures

The Hilbertian Tensor Norm and Entangled Two-Prover Games

We study tensor norms over Banach spaces and their relations to quantum information theory, in particular their connection with two-prover games. We consider a version of the Hilbertian tensor norm $\gamma_2$ and its dual $\gamma_2^*$ that allow us to consider games with arbitrary output alphabet sizes. We establish direct-product theorems and prove a generalized Grothendieck inequality for these tensor norms. Furthermore, we investigate the connection between the Hilbertian tensor norm and the set of quantum probability distributions, and show two applications to quantum information theory: firstly, we give an alternative proof of the perfect parallel repetition theorem for entangled XOR games; and secondly, we prove a new upper bound on the ratio between the entangled and the classical value of two-prover games.Comment: 33 pages, some of the results have been obtained independently in arXiv:1007.3043v2, v2: an error in Theorem 4 has been corrected; Section 6 rewritten, v3: completely rewritten in order to improve readability; title changed; references added; published versio

Dense active matter model of motion patterns in confluent cell monolayers

Epithelial cell monolayers show remarkable displacement and velocity correlations over distances of ten or more cell sizes that are reminiscent of supercooled liquids and active nematics. We show that many observed features can be described within the framework of dense active matter, and argue that persistent uncoordinated cell motility coupled to the collective elastic modes of the cell sheet is sufficient to produce swirl-like correlations. We obtain this result using both continuum active linear elasticity and a normal modes formalism, and validate analytical predictions with numerical simulations of two agent-based cell models, soft elastic particles and the self-propelled Voronoi model together with in-vitro experiments of confluent corneal epithelial cell sheets. Simulations and normal mode analysis perfectly match when tissue-level reorganisation occurs on times longer than the persistence time of cell motility. Our analytical model quantitatively matches measured velocity correlation functions over more than a decade with a single fitting parameter.Comment: updated version accepted for publication in Nat. Com