Selective Inhibition of Heparan Sulphate and Not Chondroitin Sulphate Biosynthesis by a Small,Soluble Competitive Inhibitor

The glycosaminoglycan, heparan sulphate (HS), orchestrates many developmental processes. Yet its biological role has not yet fully been elucidated. Small molecule chemical inhibitors can be used to perturb HS function and these compounds provide cheap alternatives to genetic manipulation methods. However, existing chemical inhibition methods for HS also interfere with chondroitin sulphate (CS), complicating data interpretation of HS function. Herein, a simple method for the selective inhibition of HS biosynthesis is described. Using endogenous metabolic sugar pathways, Ac₄GalNAz produces UDP-GlcNAz, which can target HS synthesis. Cell treatment with Ac₄GalNAz resulted in defective chain elongation of the polymer and decreased HS expression. Conversely, no adverse effect on CS production was observed. The inhibition was transient and dose-dependent, affording rescue of HS expression after removal of the unnatural azido sugar. The utility of inhibition is demonstrated in cell culture and in whole organisms, demonstrating that this small molecule can be used as a tool for HS inhibition in biological systems.     

Impact of nitrogen doping of carbon nanospheres on the nickel-catalyzed hydrogenation of butyronitrile

Three nickel catalysts supported on carbon and nitrogen-doped carbon nanospheres have been prepared by deposition-precipitation (DP) with urea (ca. 2% w/w). The nanospheres were prepared by thermal pyrolysis of benzene (CNS_B), aniline (CNS_A) and nitrobenzene (CNS_N) and characterized by transmission electron microscopy (TEM), N₂ adsorption–desorption, temperature-programmed oxidation (TPO), X-ray diffraction (XRD), elemental (CHN) analysis, X-ray photoelectron spectroscopy (XPS), temperature-programmed decomposition (TPD) and acid/base titrations, revealing different graphitic characteristics and different distribution of nitrogen (when present) functionalities. Upon Ni introduction, the catalysts were characterized by temperature-programmed reduction (TPR), XRD and TEM. Surface area weighted mean Ni particle diameters (post activation at 603 K) were in the range 10.5–18.2 nm. Ni particle size exhibited a big dependence on CNS nitrogen doping, where nitrogen introduction, essentially in the quaternary form, enhanced metal sintering by enriching the surface electron density of the support. The catalysts were tested in the gas phase hydrogenation of butyronitrile (T = 493 K). Extracted specific reaction rates in the steady state followed the sequence: Ni/CNS_B < Ni/CNS_A < Ni/CNS_N. When the active metal was physically mixed with the support, the following sequence was obtained: Ni + CNS_B < Ni + CNS_A < Ni + CNS_N. Our results demonstrate that doping carbon nanospheres with nitrogen strongly impacts on reactant adsorption and metal sintering, both critical aspects in the hydrogenation of nitriles. Selectivity was not sensitive to the support (or the physical mixture) employed and was in all cases close to 100% to the primary amine.     

Activation of the Interleukin-33/ST2 Pathway Exerts Deleterious Effects in Myxomatous Mitral Valve Disease

Mitral valve disease (MVD) is a frequent cause of heart failure and death worldwide, but its etiopathogenesis is not fully understood. Interleukin (IL)-33 regulates inflammation and thrombosis in the vascular endothelium and may play a role in the atherosclerotic process, but its role in mitral valve has not been investigated. We aim to explore IL-33 as a possible inductor of myxomatous degeneration in human mitral valves. We enrolled 103 patients suffering from severe mitral regurgitation due to myxomatous degeneration undergoing mitral valve replacement. Immunohistochemistry of the resected leaflets showed IL-33 and ST2 expression in both valve interstitial cells (VICs) and valve endothelial cells (VECs). Positive correlations were found between the levels of IL-33 and molecules implicated in the development of myxomatous MVD, such as proteoglycans, extracellular matrix remodeling enzymes (matrix metalloproteinases and their tissue inhibitors), inflammatory and fibrotic markers. Stimulation of single cell cultures of VICs and VECs with recombinant human IL-33 induced the expression of activated VIC markers, endothelial–mesenchymal transition of VECs, proteoglycan synthesis, inflammatory molecules and extracellular matrix turnover. Our findings suggest that the IL-33/ST2 system may be involved in the development of myxomatous MVD by enhancing extracellular matrix remodeling.     

Targeting Fatty Acid-Binding Protein 4 Improves Pathologic Features of Aortic Stenosis

Aortic stenosis (AS) is a fibrocalcific disease of the aortic valves (AVs). Sex-differences in AS pathophysiology have recently been described. High levels of fatty acid-binding protein 4 (FAPB4) in atherosclerotic plaques have been associated with increased local inflammation, endothelial dysfunction, and plaque vulnerability. FABP4 pharmacological blockade has been shown to be effective for the treatment of atherosclerosis by modulating metabolic and inflammatory pathways. We aimed to analyze the sex-specific expression of FABP4 in AS and its potential role as a therapeutic target. A total of 226 patients (61.5% men) with severe AS undergoing surgical AV replacement were recruited. The FABP4 levels were increased in the AVs of AS patients compared to the control subjects, showing greater expression in the fibrocalcific regions. Male AVs exhibited higher levels of FABP4 compared to females, correlating with markers of inflammation (IL-6, Rantes), apoptosis (Bax, caspase-3, Bcl-2), and calcification (IL-8, BMP-2 and BMP-4). VICs derived from AS patients showed the basal expression of FABP4 in vitro. Osteogenic media induced upregulation of intracellular and secreted FABP4 levels in male VICs after 7 days, along with increased levels of inflammatory, pro-apoptotic, and osteogenic markers. Treatment with BMS309403, a specific inhibitor of FABP4, prevented from all of these changes. Thus, we propose FABP4 as a new sex-specific pharmacological therapeutic target in AS.     

Angiotensin-converting enzyme activity in plasma and tissues of spontaneously hypertensive rats after the short- and long-term intake of hydrolysed egg white

This paper evaluates the effects of the short- (1 g/kg) and long-term (0.5 and 1 g/kg/day) oral intake of egg white hydrolysed with pepsin (hEW) and the long-term oral intake (1 g/kg/day) of egg white (EW) on local angiotensin-converting enzyme (ACE) activities in plasma and other tissues of spontaneously hypertensive rats (SHR), as compared to the effect of the ACE inhibitor prototype captopril. The rats treated with hEW were classed in a different group than the control rats and the rats treated with EW by cluster analysis, taking into account their tissue ACE activities and their systolic blood pressure (SBP). Principal component analysis (PCA) showed that SBP in SHR was negatively related with ACE activity in plasma and positively related with ACE activity in aorta and kidney. ACE activity in plasma significantly increased after the long-term treatment with hEW (0.5 g/kg/day). ACE activity in aorta and kidney was significantly inhibited 4 h after the short-term administration of hEW. The long-term treatment with hEW caused local effects on ACE activity in aorta, kidney and lungs that followed a pattern similar, but less pronounced, than that caused by captopril.     

Quench protection tests of a cryocooler cooled 6 T NbTi superconducting magnet by an active power method

When a quench occurs in a superconducting magnet, excessive joule heating may damage the magnet. We have presented the quench protection system based on an active power method. Our previous quench protection tests have been carried out for small superconducting magnets whose self inductances are less than several hundred mH to verify principles of our proposed system. In this paper, we present experimental results of quench protection tests of a cryocooler cooled 6 T NbTi superconducting magnet (self inductance 15.5 H), which is a commercial size magnet made by Tamakawa Co., Ltd. We confirmed that our proposed system could inhibit the maximum temperature of the superconducting magnet (initial temperature 4.3 K) after the quench to less than about 44 K at operation magnetic field 5.5 T. Experimental results suggest that our proposed system is useful for practical used superconducting magnets.     

The Core Curriculum on Childhood Trauma: A tool for training a trauma-informed workforce.

Recognition of the nationwide high prevalence of psychological trauma in children and adolescents, combined with increasing awareness of the far-reaching adverse consequences of childhood trauma, have led to calls to develop a trauma-informed mental health workforce. We describe the initial pilot test of the Core Concepts portion of the Core Curriculum on Childhood Trauma, as conducted in a large graduate school of social work. The Core Curriculum uses detailed case vignettes of trauma-exposed youth and families, combined with problem-based learning methods, to promote two primary learning aims: (a) to enhance the development of foundational trauma-related conceptual knowledge, and (b) to accelerate the acquisition of trauma-informed clinical reasoning and clinical judgment. Vignettes are presented in segments to simulate gathering, organizing, drawing meaning from, and making decisions based on information in professional practice. After each segment, the facilitator helps learners to summarize relevant facts, develop hunches and hypotheses, identify learning issues, and plan next steps. The Curriculum was very favorably received by students and was associated with marked increases in self-efficacy in applying the Core Concepts to work with trauma-exposed youth and families. We discuss ways in which the Curriculum can be used, especially as a foundation for training in specific evidence-based treatment protocols, to help prepare a national mental health workforce capable of implementing trauma-informed evidence-based practice. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Evaporative Cooling Heat Transfer of Water From Hierarchically Porous Aluminum Coating

A study of evaporative cooling of water was conducted using dual-scale hierarchically porous aluminum coating. The coating was created by brazing aluminum powders to a flat aluminum plate. The effects of particle size and thickness on evaporative heat transfer were investigated using average aluminum particle diameters of 27, 70, and 114 µm and average coating thicknesses of 560, 720, and 1200 µm. Constant ambient temperature of 24°C and relative humidity of 50% were provided throughout the study. Evaporative cooling tests on the coated surfaces were compared to the plain surface. Tested dual-scale porous coatings enhanced evaporative heat transfer significantly, compared to that of the plain surface, due to the effective wicking of water to the entire heated area. With particle size increase, both the wickability and dryout heat flux were significantly increased. The dryout heat flux with the particle size of 114 µm was 3.2 times higher than that with the particle size of 27 µm. At the fixed particle size of 70 µm the dryout heat flux increased as thickness increased, which resulted in the maximum dryout heat flux of 10.6 kW/m² and the maximum heat transfer coefficient of 251 W/m²K at the coating thickness of 1200 µm.     

Relationship between metabolic hormones and ovulation of dominant follicle during the first follicular wave post-partum in high-producing dairy cows

Recent studies suggest that IGF-I is a crucial regulatory factor in follicular growth during early post-partum period. The aim of the present study was to determine in detail the changing profiles of metabolic and reproductive hormones in relation to ovulation of the dominant follicle (DF) of the first follicular wave post-partum in high-producing dairy cows. Plasma concentrations of related hormones in 22 multiparous Holstein cows were measured from 4 weeks pre-partum to 3 weeks post-partum, and the development of DF was observed with colour Doppler ultrasound. Thirteen cows showed ovulation by 15.2 days post-partum. Anovulatory cows showed higher GH and lower IGF-I levels than those in ovulatory cows during the peri-partum period. Each DF developed similarly, and a clear blood flow in the follicle wall was observed despite ovulation or anovulation. In addition, detailed endocrine profiles were analyzed in 9 out of the 22 cows. Five cows showed an increase in plasma oestradiol-17beta (E2) with follicular growth followed by E2 peak, LH surge and ovulation. In these cows, plasma IGF-I concentrations remained high until 10 days post-partum followed by a gradual decrease. Subsequently, the insulin level increased together with the E2 peak towards ovulation. These profiles were not observed in anovulatory cows. In conclusion, our data strongly support the concept that IGF-I and insulin represent 'metabolic signals' of the resumption of ovarian function post-partum in high-producing dairy cows. Moreover, we provide the first visual evidence that both ovulatory and anovulatory DFs of the first follicular wave post-partum are similarly supplied with active blood flow.