Infants with Down syndrome (DS) or Trisomy 21, are at high risk for developing pulmonary arterial hypertension (PAH), but mechanisms that increase susceptibility are poorly understood. Laboratory ...studies have shown that early disruption of angiogenesis during development impairs vascular and alveolar growth and causes PAH. Human chromosome 21 encodes known anti-angiogenic factors, including collagen18a1 (endostatin, ES), ß-amyloid peptide (BAP) and Down Syndrome Critical Region 1 (DSCR-1). Therefore, we hypothesized that fetal lungs from subjects with DS are characterized by early over-expression of anti-angiogenic factors and have abnormal lung vascular growth in utero.
Human fetal lung tissue from DS and non-DS subjects were obtained from a biorepository. Quantitative reverse transcriptase PCR (qRT-PCR) was performed to assay 84 angiogenesis-associated genes and individual qRT-PCR was performed for ES, amyloid protein precursor (APP) and DSCR1. Western blot analysis (WBA) was used to assay lung ES, APP and DSCR-1 protein contents. Lung vessel density and wall thickness were determined by morphometric analysis.
The angiogenesis array identified up-regulation of three anti-angiogenic genes: COL18A1 (ES), COL4A3 (tumstatin) and TIMP3 (tissue inhibitor of metallopeptidase 3) in DS lungs. Single qRT-PCR and WBA showed striking elevations of ES and APP mRNA (p = 0.022 and p = 0.001) and protein (p = 0.040 and p = 0.002; respectively). Vessel density was reduced (p = 0.041) and vessel wall thickness was increased in DS lung tissue (p = 0.033) when compared to non-DS subjects.
We conclude that lung anti-angiogenic factors, including COL18A1 (ES), COL4A3, TIMP3 and APP are over-expressed and fetal lung vessel growth is decreased in subjects with DS. We speculate that increased fetal lung anti-angiogenic factor expression due to trisomy 21 impairs lung vascular growth and signaling, which impairs alveolarization and contributes to high risk for PAH during infancy.
Nonassociative structures have appeared in the study of D‐branes in curved backgrounds. In recent work, string theory backgrounds involving three‐form fluxes, where such structures show up, have been ...studied in more detail. We point out that under certain assumptions these nonassociative structures coincide with nonassociative Malcev algebras which had appeared in the quantum mechanics of systems with non‐vanishing three‐cocycles, such as a point particle moving in the field of a magnetic charge. We generalize the corresponding Malcev algebras to include electric as well as magnetic charges. These structures find their classical counterpart in the theory of Poisson‐Malcev algebras and their generalizations. We also study their connection to Stueckelberg's generalized Poisson brackets that do not obey the Jacobi identity and point out that nonassociative string theory with a fundamental length corresponds to a realization of his goal to find a non‐linear extension of quantum mechanics with a fundamental length. Similar nonassociative structures are also known to appear in the cubic formulation of closed string field theory in terms of open string fields, leading us to conjecture a natural string‐field theoretic generalization of the AdS/CFT‐like (holographic) duality.
Nonassociative structures have appeared in the study of D‐branes in curved backgrounds. In recent work, string theory backgrounds involving three‐form fluxes, where such structures show up, have been studied in some detail. Here it is pointed out that under certain assumptions these nonassociative structures coincide with nonassociative Malcev algebras. These are generalized to include electric as well as magnetic charges. Their connection to Stueckelberg's generalized Poisson brackets that do not obey the Jacobi identity is investigated. The authors conjecture a natural string‐field theoretic generalization of the AdS/CFT‐like (holographic)duality.
The kinetics of structural transformations of the Fe₇₅Ni₂Si₈B₁₃C₂ amorphous alloy under non-isothermal conditions was studied. It was shown that the amorphous alloy was stable up to 723K, when ...multi-step structural transformations start, involving formation of stable α-Fe(Si) and Fe₂B crystalline phases, and a metastable Fe₁₅Si₃B₂ phase, their growth and the decomposition of the metastable phase into the two stable phases. Peakfit software was used to resolve the overlapping peaks corresponding to different crystallization steps, at different heating rates. The kinetic parameters corresponding to each of the steps were evaluated and kinetic triplet for every single step was established (g(α)=−ln(1−α)¹/³, Eₐ=375.1±0.8kJ/mol and lnA=56.2±1.0 for step 1; Eₐ=341.6±0.5kJ/mol and lnA=49.3±0.5 for step 2). The effects of structural transformations on the established kinetic model were discussed in detail.
The structural transformations of the Fe75Ni2Si8B13C2 amorphous alloy under non-isothermal as well as under isothermal conditions were studied. The amorphous alloy was stable up to a temperature of ...723 K when the multi-step structural transformation began. The primary crystallization starts already at 723 K by forming FexSi phase in amorphous matrix. At higher temperatures (between 780 and 800 K) beside the FexSi phase, the presence of the boron-iron-silicon phase (B2Fe15Si3) as well as the iron-boron (Fe2B) phase was detected. At higher temperatures the presence of only two phases, FexSi and Fe2B, was confirmed. The Fe content in the formed FexSi phase was determined as 81% (at 1273 K) and 86 % (at 780 K). The kinetic parameters of crystallization processes were determined by Kissinger and Ozawa methods.
Myopathies decrease muscle functionality. Mutations in ryanodine receptor 1 (RyR1) are often associated with myopathies with microscopic core-like structures in the muscle fiber. In this study, we ...identify a mouse RyR1 model in which heterozygous animals display clinical and pathological hallmarks of myopathy with core-like structures. The RyR1 mutation decreases sensitivity to activated calcium release and myoplasmic calcium levels, subsequently affecting mitochondrial calcium and ATP production. Mutant muscle shows a persistent potassium leak and disrupted expression of regulators of potassium homeostasis. Inhibition of KATP channels or increasing interstitial potassium by diet or FDA-approved drugs can reverse the muscle weakness, fatigue-like physiology and pathology. We identify regulators of potassium homeostasis as biomarkers of disease that may reveal therapeutic targets in human patients with myopathy of central core disease (CCD). Altogether, our results suggest that amelioration of potassium leaks through potassium homeostasis mechanisms may minimize muscle damage of myopathies due to certain RyR1 mutations.
Effect of heat treatment on mechanical behavior of Fe sub(89.8)Ni sub(1.5)Si sub(5.2)B sub(3)C sub(0.5) amorphous alloy was investigated by measuring microhardness. It was shown that the as-prepared ...amorphous alloy has an unexpectedly high microhardness. This can be attributed not only to boron dispersed in the alloy, but also to the structure which exhibits aspects of a nanocomposite of nanoparticles dispersed in an amorphous matrix. As the alloy crystallizes at temperatures above 540 degree C, microhardness decreases continuously as a function of heating temperature. This is attributed to separation of boron out of the amorphous matrix into nanocrystals of Fe sub(2)B phase. Further decrease in microhardness is attributed to crystallite growth with the accompanying change in the dominant nature of the interfaces from amorphous/crystal to crystal/crystal, and creation of a porous structure. When the crystallization is complete, the alloy exhibits microhardness close to that of a hypothetical mixture of alpha -Fe and Fe sub(2)B phases of the same composition.
The thermal stability and crystallization of the Fe(8(1B(1(3Si(4)C(2) amorphous alloy were investigated in the temperature range of 300-1173K. The correlation of the DSC and X-ray diffraction data ...with the measurements of electric and magnetic properties, which are very sensitive to structural changes, has shown a complex crystallization process involving at least two overlapping steps which appeared as one sharp slightly asymmetrical crystallization peak on the DSC curve. That could mean that the entire nucleation process did not take place during the early stage of the transformation and did not become negligible afterward. In this case, the crystallization rate is not defined by only the temperature but also depends on the previous thermal history of the alloy. This could be reason why the Johnson-Mehl-Avrami model usually used for the description of crystallization involving the stage of nucleation and the stage of growth of nuclei is not valid.
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