Enzyme Replacement in Gaucher Disease

The development of enzyme replacement therapy for Gaucher disease was a triumph of translational medicine. What were the key steps in its development? What are the controversies surrounding its use

Identification of a novel mechanism of blood-brain communication during peripheral inflammation via choroid plexus-derived extracellular vesicles

Here, we identified release of extracellular vesicles (EVs) by the choroid plexus epithelium (CPE) as a new mechanism of blood-brain communication. Systemic inflammation induced an increase in EVs and associated pro-inflammatory miRNAs, including miR-146a and miR-155, in the CSF. Interestingly, this was associated with an increase in amount of multivesicular bodies (MVBs) and exosomes per MVB in the CPE cells. Additionally, we could mimic this using LPS-stimulated primary CPE cells and choroid plexus explants. These choroid plexus-derived EVs can enter the brain parenchyma and are taken up by astrocytes and microglia, inducing miRNA target repression and inflammatory gene up-regulation. Interestingly, this could be blocked in vivo by intracerebroventricular (icv) injection of an inhibitor of exosome production. Our data show that CPE cells sense and transmit information about the peripheral inflammatory status to the central nervous system (CNS) via the release of EVs into the CSF, which transfer this pro-inflammatory message to recipient brain cells. Additionally, we revealed that blockage of EV secretion decreases brain inflammation, which opens up new avenues to treat systemic inflammatory diseases such as sepsis

Expression of the Tumor Necrosis Factor Gene by Dermal Fibroblasts in Response to Ultraviolet Irradiation or Lipopolysaccharide

To examine the effects of different wavelengths of ultraviolet (UV) radiation on tumor necrosis factor (TNF) production, we took advantage of mice carrying a chloramphenicol acetyl transferase (CAT) reporter transgene bearing the entire TNF promoter and 3'-untranslated region. Aside from constitutive expression in the thymus, CAT activity was detected only in locally UVB- or UVC-irradiated skin. After UVB irradiation, markedly greater amounts of CAT activity were traced to the dermis rather than the epidermis; by contrast, almost all CAT activity was localized to the epidermis after UVC irradiation, Fibroblasts have not been shown previously to express the TNF gene, i.e., the TNF gene is highly methylated and inaccessible to exogenous modulation in 3T3 fibroblasts, However, the present report reveals that cultured dermal fibroblasts are capable of producing both CAT and TNF in response to treatment in vitro with either UVB irradiation, UVC irradiation, or lipopolysaccharide. These findings indicate that dermal fibroblasts may serve not only as a target for but also as a source of TNF

Redshift-weighted constraints on primordial non-Gaussianity from the clustering of the eBOSS DR14 quasars in Fourier space

We present constraints on local primordial non-Gaussianity (PNG), parametrized through $f^{\rm loc}_{\rm NL}$, using the Sloan Digital Sky Survey IV extended Baryon Oscillation Spectroscopic Survey Data Release 14 quasar sample. We measure and analyze the anisotropic clustering of the quasars in Fourier space, testing for the scale-dependent bias introduced by primordial non-Gaussianity on large scales. We derive and employ a power spectrum estimator using optimal weights that account for the redshift evolution of the PNG signal. We find constraints of $-51<f^{\rm loc}_{\rm NL}<21$ at 95% confidence level. These are amont the tightest constraints from Large Scale Structure (LSS) data. Our redshift weighting improves the error bar by 15% in comparison to the unweighted case. If quasars have lower response to PNG, the constraint degrades to $-81<f^{\rm loc}_{\rm NL}<26$, with a 40% improvement over the standard approach. We forecast that the full eBOSS dataset could reach $\sigma_{f^{\rm loc}_{\rm NL}}\simeq 5\text{-}8$ using optimal methods and full range of scales.Comment: 28 pages, 12 figures. Comments welcome

An improved model for the nonlinear velocity power spectrum

The velocity divergence power spectrum is a key ingredient in modelling redshift space distortion effects on quasi-linear and nonlinear scales. We present an improved model for the z=0 velocity divergence auto and cross power spectrum which was originally suggested by Jennings et al. 2011. Using numerical simulations we measure the velocity fields using a Delaunay tesselation and obtain an accurate prediction of the velocity divergence power spectrum on scales k < 1 hMpc^{-1}. We use this to update the model which is now accurate to 2% for both P_{\theta \theta} and P_{\theta \delta} at z=0 on scales k <0.7 hMpc^{-1} and k <0.5 hMpc^{-1} respectively. We find that the formula for the redshift dependence of the velocity divergence power spectra proposed by Jennings et al. 2011 recovers the measured z>0 P(k) to markedly greater accuracy with the new model. The nonlinear P_{\theta \theta} and P_{\theta \delta} at z =1 are recovered accurately to better than 2% on scales k<0.2 hMpc^{-1}. Recently it was shown that the velocity field shows larger differences between modified gravity cosmologies and \Lambda CDM compared to the matter field. An accurate model for the velocity divergence power spectrum, such as the one presented here, is a valuable tool for analysing redshift space distortion effects in future galaxy surveys and for constraining deviations from general relativity.Comment: 5 pages, 2 figures, Accepted for publication in MNRA

The role of nitric-oxide-synthase-derived nitric oxide in multicellular traits of Bacillus subtilis 3610: biofilm formation, swarming, and dispersal

<p>Abstract</p> <p>Background</p> <p><it>Bacillus subtilis </it>3610 displays multicellular traits as it forms structurally complex biofilms and swarms on solid surfaces. In addition, <it>B. subtilis </it>encodes and expresses nitric oxide synthase (NOS), an enzyme that is known to enable NO-mediated intercellular signalling in multicellular eukaryotes. In this study, we tested the hypothesis that NOS-derived NO is involved in the coordination of multicellularity in <it>B. subtilis </it>3610.</p> <p>Results</p> <p>We show that <it>B. subtilis </it>3610 produces intracellular NO <it>via </it>NOS activity by combining Confocal Laser Scanning Microscopy with the NO sensitive dye copper fluorescein (CuFL). We further investigated the influence of NOS-derived NO and exogenously supplied NO on the formation of biofilms, swarming motility and biofilm dispersal. These experiments showed that neither the suppression of NO formation with specific NOS inhibitors, NO scavengers or deletion of the <it>nos </it>gene, nor the exogenous addition of NO with NO donors affected (i) biofilm development, (ii) mature biofilm structure, and (iii) swarming motility in a qualitative and quantitative manner. In contrast, the <it>nos </it>knock-out and wild-type cells with inhibited NOS displayed strongly enhanced biofilm dispersal.</p> <p>Conclusion</p> <p>The results suggest that biofilm formation and swarming motility in <it>B. subtilis </it>represent complex multicellular processes that do not employ NO signalling and are remarkably robust against interference of NO. Rather, the function of NOS-derived NO in <it>B. subtilis </it>might be specific for cytoprotection against oxidative stress as has been proposed earlier. The influence of NOS-derived NO on dispersal of <it>B. subtilis </it>from biofilms might be associated to its well-known function in coordinating the transition from oxic to anoxic conditions. Here, NOS-derived NO might be involved in fine-tuning the cellular decision-making between adaptation of the metabolism to (anoxic) conditions in the biofilm or dispersal from the biofilm.</p

Ambivalence in narrative therapy: a comparison between recovered and unchanged cases

Research on the identification of poor outcome predictors is crucial for the prevention of therapeutic failure. Previous research suggests that clients’ persistent ambivalence is one possible path to unsuccessful psychotherapy. The present study analyses ambivalence—here operationalized as return-tothe-problem markers (RPMs)—in five recovered and five unchanged cases of narrative psychotherapy for major depression. The results suggest that both recovered and unchanged cases presented a similar proportion of RPMs at baseline and a decreasing pattern of these ambivalence markers throughout therapy. However, the decreasing was more accentuated in recovered than in unchanged cases, and at the end of the treatment, the proportion of RPMs of the unchanged cases was significantly higher. The results are discussed in light of previous research on ambivalence in psychotherapy, focusing on the meaning of ambivalence and its clinical implications

Fano resonances and decoherence in transport through quantum dots

A tunable microwave scattering device is presented which allows the controlled variation of Fano line shape parameters in transmission through quantum billiards. We observe a non-monotonic evolution of resonance parameters that is explained in terms of interacting resonances. The dissipation of radiation in the cavity walls leads to decoherence and thus to a modification of the Fano profile. We show that the imaginary part of the complex Fano q-parameter allows to determine the absorption constant of the cavity. Our theoretical results demonstrate further that the two decohering mechanisms, dephasing and dissipation, are equivalent in terms of their effect on the evolution of Fano resonance lineshapes.Comment: 9 pages, 7 figures, submitted to Physica E (conference proceedings

Transient deformations in the Suez-Sinai area from GPS observations

We analyze data from four GPS campaigns carried out between 1997 and 2002 on a network of 11 sites in the Suez-Sinai, the area of collision between the African and the Arabian plates. This is the key area to understand how and in which way Sinai behaves like a sub-plate of the African plate and the role played between seismic and geodetic (long term) deformation release. Our analysis shows that, on average, the Suez-Sinai area motion (in terms of ITRF00 velocities) matches African plate motion (NNR-NUVEL-1A model). However, the baseline length variations show transient deformations in Sinai and across the Gulf of Suez, reaching up a maximum value of about 1.5 cm in five years. Since current geodynamical models do not predict significant tectonic deformation in this area, we worked under the hypothesis that a contribute may be due to post-seismic relaxation. Under this hypothesis, we compared the baselines length variations with the post-seismic relaxation field associated with five major local earthquakes occurred in the area, testing two different viscoelastic models. Our results show that the transient deformations are better modelled for viscosity values of 1018 Pa s in the lower crust and 1020 Pa s in the asthenosphere. However, since the modelled post-seismic effect results modest and a certain amount of the detected deformation is not accounted for, we think that an improved modelling should take into account the lateral heterogeneities of crust and upper mantle structures

Kernicterus by glucose-6-phosphate dehydrogenase deficiency: a case report and review of the literature

<p>Abstract</p> <p>Introduction</p> <p>Glucose-6-phosphate dehydrogenase deficiency is an X-linked recessive disease that causes acute or chronic hemolytic anemia and potentially leads to severe jaundice in response to oxidative agents. This deficiency is the most common human innate error of metabolism, affecting more than 400 million people worldwide.</p> <p>Case presentation</p> <p>Here, we present the first documented case of kernicterus in Panama, in a glucose-6-phosphate dehydrogenase-deficient newborn clothed in naphthalene-impregnated garments, resulting in reduced psychomotor development, neurosensory hypoacousia, absence of speech and poor reflex of the pupil to light.</p> <p>Conclusion</p> <p>Mutational analysis revealed the glucose-6-phosphate dehydrogenase Mediterranean polymorphic variant, which explained the development of kernicterus after exposition of naphthalene. As the use of naphthalene in stored clothes is a common practice, glucose-6-phosphate dehydrogenase testing in neonatal screening could prevent severe clinical consequences.</p