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 , ,

Low-mass X-ray binaries and globular clusters streamers and ARCS in NGC 4278

We report significant inhomogeneities in the projected two-dimensional spatial distributions of low-mass X-ray binaries (LMXBs) and globular clusters (GCs) of the intermediate mass elliptical galaxy NGC 4278. In the inner region of NGC 4278, a significant arc-like excess of LMXBs extending south of the center at ∼50″ in the western side of the galaxy can be associated with a similar overdensity of the spatial distribution of red GCs from Brassington et al. Using a recent catalog of GCs produced by Usher et al. and covering the whole field of the NGC 4278 galaxy, we have discovered two other significant density structures outside the D 25 isophote to the W and E of the center of NGC 4278, associated with an overdensity and an underdensity, respectively. We discuss the nature of these structures in the context of the similar spatial inhomogeneities discovered in the LMXBs and GCs populations of NGC 4649 and NGC 4261, respectively. These features suggest streamers from disrupted and accreted dwarf companions.Peer reviewe

Effects of Drought on Mortality in Macro Urban Areas of Brazil Between 2000 and 2019.

A significant fraction of Brazil's population has been exposed to drought in recent years, a situation that is expected to worsen in frequency and intensity due to climate change. This constitutes a current key environmental health concern, especially in densely urban areas such as several big cities and suburbs. For the first time, a comprehensive assessment of the short-term drought effects on weekly non-external, circulatory, and respiratory mortality was conducted in 13 major Brazilian macro-urban areas across 2000-2019. We applied quasi-Poisson regression models adjusted by temperature to explore the association between drought (defined by the Standardized Precipitation-Evapotranspiration Index) and the different mortality causes by location, sex, and age groups. We next conducted multivariate meta-analytical models separated by cause and population groups to pool individual estimates. Impact measures were expressed as the attributable fractions among the exposed population, from the relative risks (RRs). Overall, a positive association between drought exposure and mortality was evidenced in the total population, with RRs varying from 1.003 [95% CI: 0.999-1.007] to 1.010 [0.996-1.025] for non-external mortality related to moderate and extreme drought conditions, from 1.002 [0.997-1.007] to 1.008 [0.991-1.026] for circulatory mortality, and from 1.004 [0.995-1.013] to 1.013 [0.983-1.044] for respiratory mortality. Females, children, and the elderly population were the most affected groups, for whom a robust positive association was found. The study also revealed high heterogeneity between locations. We suggest that policies and action plans should pay special attention to vulnerable populations to promote efficient measures to reduce vulnerability and risks associated with droughts

Dispersion Entropy: A Measure of Electrohysterographic Complexity for Preterm Labor Discrimination

[EN] Although preterm labor is a major cause of neonatal death and often leaves health sequels in the survivors, there are no accurate and reliable clinical tools for preterm labor prediction. The Electrohysterogram (EHG) has arisen as a promising alternative that provides relevant information on uterine activity that could be useful in predicting preterm labor. In this work, we optimized and assessed the performance of the Dispersion Entropy (DispEn) metric and compared it to conventional Sample Entropy (SampEn) in EHG recordings to discriminate term from preterm deliveries. For this, we used the two public databases TPEHG and TPEHGT DS of EHG recordings collected from women during regular checkups. The 10th, 50th and 90th percentiles of entropy metrics were computed on whole (WBW) and fast wave high (FWH) EHG bandwidths, sweeping the DispEn and SampEn internal parameters to optimize term/preterm discrimination. The results revealed that for both the FWH and WBW bandwidths the best separability was reached when computing the 10th percentile, achieving a p-value (0.00007) for DispEn in FWH, c = 7 and m = 2, associated with lower complexity preterm deliveries, indicating that DispEn is a promising parameter for preterm labor prediction.This work was supported by the Spanish ministry of economy and competitiveness, the European Regional Development Fund (MCIU/AEI/FEDER, UE RTI2018-094449-A-I00-AR) and the Generalitat Valenciana (AICO/2019/220).Nieto-Del-Amor, F.; Ye Lin, Y.; Garcia-Casado, J.; Díaz-Martínez, MDA.; González Martínez, M.; Monfort-Ortiz, R.; Prats-Boluda, G. (2021). Dispersion Entropy: A Measure of Electrohysterographic Complexity for Preterm Labor Discrimination. SCITEPRESS. 260-267. https://doi.org/10.5220/0010316602600267S26026

Dynamics of Weyl Scale Invariant non-BPS p=3 Branes

In this paper a Weyl scale invariant $p=3$ brane scenario is introduced, with the brane embedded in a higher dimensional bulk space with $N=1, 5D$ Super--Weyl symmetry. Its action, which describes its long wave oscillation modes into the ambient superspace and breaks the target symmetry down to the lower dimensional Weyl W(1,3) symmetry, is constructed by the approach of coset method.Comment: 12 pages, modified versio

The Cluster of Blue Stars Surrounding the M31 Nuclear Black Hole

We obtained U_330 and B band images of the M31 nucleus using the High Resolution Camera of the Advanced Camera for Surveys on board the Hubble Space Telescope (HST). The spatial resolution in the U_330-band, 0.03" FWHM, or 0.1 pc at M31, is sufficient to resolve the outskirts of the compact cluster (P3) of UV-bright stars surrounding the M31 black hole. The center of the cluster is marked by an extended source that is both brighter and redder than the other point sources within P3; it is likely to be a blend of several bright stars. We hypothesize that it marks the location of the M31 black hole. Both stellar photometry and a surface brightness fluctuation analysis, show that the P3 stellar population is consistent with early-type main sequence stars formed in a ~100 - ~200 Myr old starburst population. Evolutionary tracks of post early asymptotic giant-branch stars, associated with late-stage evolution of an old population, also traverse the U and U-B domain occupied by the P3 stars; but we argue that only a few stars could be accounted for that way. PEAGB evolution is very rapid, and there is no progenitor population of red giants associated with P3. The result that P3 comprises young stars is consistent with inferences from earlier HST observations of the integrated light of the cluster. Like the Milky Way, M31 harbors a black hole closely surrounded by apparently young stars.Comment: 29 pages, 11 figures (3 color); Astrophysical Journal accepte

An Imaging Survey of Early-Type Barred Galaxies

This paper presents the results of a high-resolution imaging survey, using both ground-based and Hubble Space Telescope images, of a complete sample of nearby barred S0--Sa galaxies in the field, with a particular emphasis on identifying and measuring central structures within the bars: secondary bars, inner disks, nuclear rings and spirals, and off-plane dust. A discussion of the frequency and statistical properties of the various types of inner structures has already been published. Here, we present the data for the individual galaxies and measurements of their bars and inner structures. We set out the methods we use to find and measure these structures, and how we discriminate between them. In particular, we discuss some of the deficiencies of ellipse fitting of the isophotes, which by itself cannot always distinguish between bars, rings, spirals, and dust, and which can produce erroneous measurements of bar sizes and orientations.Comment: LaTeX, 66 pages (including 42 figures, 36 in color). To appear in The Astrophysical Journal Supplement. Full-resolution and text-only versions available at http://www.iac.es/galeria/erwin/research

Iron bioavailability in two commercial cultivars of wheat: a comparison between wholegrain and white flour and the effects of nicotianamine and 2'-deoxymugineic acid on iron uptake into Caco-2 cells

Iron bioavailability in unleavened white and wholegrain bread made from two commercial wheat varieties was assessed by measuring ferritin production in Caco-2 cells. The breads were subjected to simulated gastrointestinal digestion and the digests applied to the Caco-2 cells. Although Riband grain contained a lower iron concentration than Rialto, iron bioavailability was higher. No iron was taken up by the cells from white bread made from Rialto flour or from wholegrain bread from either variety, but Riband white bread produced a small ferritin response. The results probably relate to differences in phytate content of the breads, although iron in soluble monoferric phytate was demonstrated to be bioavailable in the cell model. Nicotianamine, an iron chelator in plants involved in iron transport, was a more potent enhancer of iron uptake into Caco-2 cells than ascorbic acid or 2'-deoxymugineic acid, another metal chelator present in plants

Iso-spectral potential and inflationary quantum cosmology

Using the factorization approach of quantum mechanics, we obtain a family of isospectral scalar potentials for power law inflationary cosmology. The construction is based on a scattering Wheeler-DeWitt solution. These iso-spectrals have new features, they give a mechanism to end inflation, as well as the possibility to have new inflationary epochs. The procedure can be extended to other cosmological models.Comment: 14 pages, 5 figure