Micro-computed tomography (CT) is a non-invasive alternative to conventional macroscopic dissection for the evaluation of human fetal cardiac anatomy. This paper aims to systematically review the ...literature regarding the use of micro-CT to examine human fetal hearts, to illustrate its educational and research implications and to explain its possible directions for the future. A systematic literature review was conducted following the PRISMA statement to identify publications concerning micro-CT applications for the isolated human fetal heart. The search strategy identified nine eligible studies. Micro-CT is technically feasible for postmortem examination of the human fetal heart coming from early and late termination of pregnancy. It reaches high diagnostic accuracy, and it seems to perform better than autopsy in small samples or in the case of early termination of pregnancy. Applications derived from micro-CT allow multiple off-time evaluations and interdisciplinary comparisons for educational purposes and research perspectives in biological and bioengineering domains.
Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder caused by the expression of mutant huntingtin protein (Htt). Suppression of Htt expression, using RNA interference, ...might be an effective therapy. However, if reduction of wild-type protein is not well tolerated in the brain, it may be necessary to suppress just the product of the mutant allele. We present a small interfering RNA (siRNA) that selectively reduces the endogenous mRNA for a heterozygous HD donor's pathogenic allele by approximately 80% by specifically targeting a single-nucleotide polymorphism (SNP) located several thousand bases downstream from the disease-causing mutation. In addition, we show selective suppression of endogenous mutant Htt protein, using this siRNA. We further present a method, using just a heterozygous patient's own mRNA, to determine which SNP variants correspond to the mutant allele. The method may be useful in any disorder in which a targeted SNP is far downstream from the pathogenic mutation. These results indicate that allele-specific treatment for Huntington's disease may be clinically feasible and practical.
This work explores avenues toward PCP pincer complexes with acyclic diaminocarbene central moieties that are suitable for ligand-assisted reactivity involving the carbene carbon. For this purpose, ...diphosphine chelating ligands 1 and 2, with bis(imidazolyl)methyl and bis(pyrazolyl)methyl backbones, respectively, were prepared in two high-yield synthetic steps. Nickel(II) and platinum(II) dihalide complexes 3 and 6, incorporating 1, were prepared and converted into PCP pincer ligands 5 and 7 upon deprotonation with KHMDS. Chelated nickel(I) complex 4 was obtained as a byproduct to 3. Although the solid-state structures of 5 and 7 presented geometric strain at the diaminomethyl carbon, this moiety could not be converted into a diaminocarbene by proton or hydride abstraction. 7 could be converted into platinum(IV) analog 8 by oxidation with PhICl2. Ligand 2 proved more versatile than 1, or less dependable in its behavior, generating P,N-chelating cobalt(II) dibromide complex 9. Easily accessible ligands 1 and 2 provide a new and versatile PCP pincer platform.
We use the Dieterich (1994) physics‐based approach to simulate the spatiotemporal evolution of seismicity caused by stress changes applied to an infinite population of nucleating patches modeled ...through a rate‐ and state‐dependent friction law. According to this model, seismicity rate changes depend on the amplitude of stress perturbation, the physical constitutive properties of faults (represented by the parameter Aσ), the stressing rate, and the background seismicity rate of the study area. In order to apply this model in a predictive manner, we need to understand the impact of physical model parameters and the correlations between them. First, we discuss different definitions of the reference seismicity rate and show their impact on the computed rate of earthquake production for the 1992 Landers earthquake sequence as a case study. Furthermore, we demonstrate that all model parameters are strongly correlated for physical and statistical reasons. We discuss this correlation, emphasizing that the estimations of the background seismicity rate, stressing rate, and Aσ are strongly correlated to reproduce the observed aftershock productivity. Our analytically derived relation demonstrates the impact of these model parameters on the Omori‐like aftershock decay: the c value and the productivity of the Omori law, implying a p value smaller than or equal to 1. Finally, we discuss an optimal strategy to constrain model parameters for near‐real‐time forecasts.
► The role of RBF technique in inter-grid interpolation and mesh motion is investigated. ► Interface data transfer for general multi-physics/multi-domain problems is analyzed. ► In the framework of ...FSI problems, the properties of different RBF bases are compared. ► Implementation issues and test cases are discussed to assess the proposed methodology.
When addressing multi-domain/multi-physics problems, the correct exchange of mathematical information at subdomain interfaces is crucial. In this paper, such transfer is analyzed in the particular framework of a fluid-structure interaction (FSI) problem. A genuine FEM–FEM formulation is considered firstly, followed by a mixed FVM–FEM formulation. In both cases, we focus on two critical issues: how to interpolate numerical quantities at the interface, and how to achieve the property of conservation of energy transfer. In the second part of this work, we analyze the use of radial basis functions (RBF) to handle both mesh motion and interpolation of numerical variables over non-matching interface grids. Different kinds of radial basis functions are considered and numerical tests comparing their performances in terms of accuracy and stability are presented and discussed.
We report that in breast cancer cells, tyrosine phosphorylation of the estradiol receptor alpha (ERalpha) by Src regulates cytoplasmic localization of the receptor and DNA synthesis. Inhibition of ...Src or use of a peptide mimicking the ERalpha p-Tyr537 sequence abolishes ERalpha tyrosine phosphorylation and traps the receptor in nuclei of estradiol-treated MCF-7 cells. An ERalpha mutant carrying a mutation of Tyr537 to phenylalanine (ER537F) persistently localizes in nuclei of various cell types. In contrast with ERalpha wt, ER537F does not associate with Ran and its interaction with Crm1 is insensitive to estradiol. Thus, independently of estradiol, ER537F is retained in nuclei, where it entangles FKHR-driving cell cycle arrest. Chromatin immunoprecipitation analysis reveals that overexpression of ER537F in breast cancer cells enhances FKHR interaction with cyclin D1 promoter. This mutant also counteracts cell transformation by the activated forms of Src or PI3-K. In conclusion, in addition to regulating receptor localization, ERalpha phosphorylation by Src is required for hormone responsiveness of DNA synthesis in breast cancer cells.
Alkylation of DNA and RNA is a potentially toxic lesion that can result in mutations and even cell death. In response to alkylation damage, K63-linked polyubiquitin chains are assembled that localize ...the Alpha-ketoglutarate-dependent dioxygenase alkB homolog 3–Activating Signal Cointegrator 1 Complex Subunit (ASCC) repair complex to damage sites in the nucleus. The protein ASCC2, a subunit of the ASCC complex, selectively binds K63-linked polyubiquitin chains via its coupling of ubiquitin conjugation to ER degradation (CUE) domain. The basis for polyubiquitin-binding specificity was unclear, because CUE domains in other proteins typically bind a single ubiquitin and do not discriminate among different polyubiquitin linkage types. We report here that the ASCC2 CUE domain selectively binds K63-linked diubiquitin by contacting both the distal and proximal ubiquitin. The ASCC2 CUE domain binds the distal ubiquitin in a manner similar to that reported for other CUE domains bound to a single ubiquitin, whereas the contacts with the proximal ubiquitin are unique to ASCC2. Residues in the N-terminal portion of the ASCC2 α1 helix contribute to the binding interaction with the proximal ubiquitin of K63-linked diubiquitin. Mutation of residues within the N-terminal portion of the ASCC2 α1 helix decreases ASCC2 recruitment in response to DNA alkylation, supporting the functional significance of these interactions during the alkylation damage response. Our study reveals the versatility of CUE domains in ubiquitin recognition.
Aims. We aim constrain the assembly history of clusters by studying the intracluster light (ICL) properties, estimating its contribution to the fraction of baryons in stars, f∗, and understanding ...possible systematics or bias using different ICL detection techniques. Methods. We developed an automated method, GALtoICL, based on the software GALAPAGOS, to obtain a refined version of typical BCG+ICL maps. We applied this method to our test case MACS J1206.2-0847, a massive cluster located at z ~ 0.44, which is part of the CLASH sample. Using deep multiband Subaru images, we extracted the surface brightness (SB) profile of the BCG+ICL and studied the ICL morphology, color, and contribution to f∗ out to R500. We repeated the same analysis using a different definition of the ICL, SBlimit method, i.e., a SB cut-off level, to compare the results. Results. The most peculiar feature of the ICL in MACS1206 is its asymmetric radial distribution, with an excess in the SE direction and extending toward the second brightest cluster galaxy, which is a post starburst galaxy. This suggests an interaction between the BCG and this galaxy that dates back to τ ≤ 1.5 Gyr. The BCG+ICL stellar content is ~8% of M∗,500, and the (de-) projected baryon fraction in stars is f∗ = 0.0177(0.0116), in excellent agreement with recent results. The SBlimit method provides systematically higher ICL fractions and this effect is stronger at lower SB limits. This is due to the light from the outer envelopes of member galaxies that contaminate the ICL. Though more time consuming, the GALtoICL method provides safer ICL detections that are almost free of this contamination. This is one of the few ICL study at redshift z > 0.3. At completion, the CLASH/VLT program will allow us to extend this analysis to a statistically significant cluster sample spanning a wide redshift range: 0.2 ≲ z ≲ 0.6.
We present an extinction map of a similar to 1700 deg sq region that encloses the Ophiuchus, the Lupus, and the Pipe dark complexes using 42 million stars from the Two Micron All Sky Survey (2MASS) ...point source catalog. The use of a robust and optimal near-infrared method to map dust column density (NICER, described in Lombardi & Alves 2001, A&A, 377, 1023) allow us to detect extinction as low as A sub(K) = 0.05 mag with a 2-\sigma significance, and still to have a resolution of 3 arcmin on our map. We also present a novel, statistically sound method to characterize the small-scale inhomogeneities in molecular clouds. Finally, we investigate the cloud structure function, and show that significant deviations from the results predicted by turbulent models are observed.
Context.
Exoplanetary research has provided us with exciting discoveries of planets around very low-mass (VLM) stars (0.08
M
⊙
≲
M
*
≲ 0.3
M
⊙
; e.g., TRAPPIST-1 and Proxima Centauri). However, ...current theoretical models still strive to explain planet formation in these conditions and do not predict the development of giant planets. Recent high-resolution observations from the Atacama Large Millimeter/submillimeter Array (ALMA) of the disk around CIDA 1, a VLM star in Taurus, show substructures that hint at the presence of a massive planet.
Aims.
We aim to reproduce the dust ring of CIDA 1, observed in the dust continuum emission in ALMA Band 7 (0.9 mm) and Band 4 (2.1 mm), along with its
12
CO (
J
= 3−2) and
13
CO (
J
= 3−2) channel maps, assuming the structures are shaped by the interaction of the disk with a massive planet. We seek to retrieve the mass and position of the putative planet, through a global simulation that assesses planet-disk interactions to quantitatively reproduce protoplanetary disk observations of both dust and gas emission in a self-consistent way.
Methods.
Using a set of hydrodynamical simulations, we model a protoplanetary disk that hosts an embedded planet with a starting mass of between 0.1 and 4.0
M
Jup
and initially located at a distance of between 9 and 11 au from the central star. We compute the dust and gas emission using radiative transfer simulations, and, finally, we obtain the synthetic observations, treating the images as the actual ALMA observations.
Results.
Our models indicate that a planet with a minimum mass of ~1.4
M
Jup
orbiting at a distance of ~9−10 au can explain the morphology and location of the observed dust ring in Band 7 and Band 4. We match the flux of the dust emission observation with a dust-to-gas mass ratio in the disk of ~10
−2
. We are able to reproduce the low spectral index (~2) observed where the dust ring is detected, with a ~40−50% fraction of optically thick emission. Assuming a
12
CO abundance of 5 × 10
−5
and a
13
CO abundance 70 times lower, our synthetic images reproduce the morphology of the
12
CO (
J
= 3−2) and
13
CO (
J
=
3−2) observed channel maps where the cloud absorption allowed a detection. From our simulations, we estimate that a stellar mass
M
*
= 0.2
M
⊙
and a systemic velocity
v
sys
= 6.25 km s
−1
are needed to reproduce the gas rotation as retrieved from molecular line observations. Applying an empirical relation between planet mass and gap width in the dust, we predict a maximum planet mass of ~4−8
M
Jup
.
Conclusions.
Our results suggest the presence of a massive planet orbiting CIDA 1, thus challenging our understanding of planet formation around VLM stars.
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