Inhibition of DDAH1, but not DDAH2, results in apoptosis of a human trophoblast cell line in response to TRAIL.

STUDY QUESTION: Does inhibition of dimethylarginine dimethylaminohydrolase (DDAH) increase the sensitivity of trophoblasts to TRAIL-induced apoptosis? SUMMARY ANSWER: Inhibition of DDAH1, but not DDAH2, increases the sensitivity of trophoblasts to TRAIL-induced apoptosis. WHAT IS KNOWN ALREADY: Successful human pregnancy is dependent on adequate trophoblast invasion and remodelling of the maternal spiral arteries. Increased trophoblast apoptosis is seen in pregnancies complicated by pre-eclampsia. The mechanism underlying this increase is unknown. We have previously shown that nitric oxide (NO) is involved in regulating trophoblast motility and invasion, and have also demonstrated an important role for NO in regulating trophoblast sensitivity to apoptotic stimuli. DDAH is an enzyme that metabolizes asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthesis, previously shown to be elevated in the plasma of pre-eclamptic mothers. STUDY DESIGN, SIZE, DURATION: This study used the human extravillous trophoblast-derived cell line SGHPL-4 cells. All experiments were performed at least three times. PARTICIPANTS/MATERIALS, SETTING, METHODS: The effect of DDAH on trophoblast apoptosis was examined using siRNA and time-lapse microscopy. Changes in the expression of DDAH were followed by PCR and western blot analysis. Receptor expression was followed by flow cytometry. MAIN RESULTS AND THE ROLE OF CHANCE: Inhibiting the expression of DDAH1, but not DDAH2, resulted in a significant increase in the sensitivity of the EVT cell line SGHPL-4 to tumour necrosis factor related apoptosis inducing ligand (TRAIL) induced apoptosis (P < 0.01). This response could be mimicked by the addition of Asymmetric Dimethylarginine (ADMA), an endogenous inhibitor of NO synthesis and the substrate for both isoforms of DDAH. We further showed that this increased sensitivity to apoptosis is accompanied by a significant increase in the expression of TRAIL receptor 2 (TR2; P < 0.05) but not TRAIL receptor 1 (TR1). LIMITATIONS, REASONS FOR CAUTION: This study was performed only in vitro using a well characterized trophoblast cell line, SGHPL-4, derived from first trimester extravillous trophoblasts. WIDER IMPLICATIONS OF THE FINDINGS: This study provides new insight into the role of the DDAH/ADMA pathway in the regulation of trophoblast function. Both dysregulation of DDAH and the accumulation of ADMA have been associated with the development of pre-eclampsia. This is the first study to implicate the DDAH/ADMA pathway as a mechanism that might underlie the poor trophoblast invasion seen in this common pregnancy disorder. STUDY FUNDING/COMPETING INTERESTS: B.A.L. was supported by a grant from Action Medical Research UK (SP4577). A.E.W. was supported by a grant from the Wellcome Trust (091550). There are no competing interests and the authors have no conflict interest to declare

Soft-mode anisotropy in the negative thermal expansion material ReO3

We use a symmetry-motivated approach to analyse neutron pair distribution function data to investigate the character of the soft phonon modes in negative thermal expansion (NTE) material ReO3. This analysis shows that its local structure is dominated by an in-phase octahedral tilting mode and that the octahedral units are far less flexible to scissoring type deformations than in the related NTE compound ScF3. The lack of flexibility in ReO3 restricts the NTE-driving phonons to a smaller region of reciprocal space, limiting the magnitude and temperature range of NTE. These results support the idea that structural flexibility is an important factor in NTE materials. Surprisingly, our results show that the local fluctuations, even at elevated temperatures, respect the symmetry and order parameter direction of the initial pressure induced phase transition in ReO3. The result indicates that the dynamic motions associated with rigid unit modes are highly anisotropic in these systems

Signature of small rings in the Raman spectra of normal and compressed amorphous silica: A combined classical and ab initio study

We calculate the parallel (VV) and perpendicular (VH) polarized Raman spectra of amorphous silica. Model SiO2 glasses, uncompressed and compressed, were generated by a combination of classical and ab initio molecular-dynamics simulations and their dynamical matrices were computed within the framework of the density functional theory. The Raman scattering intensities were determined using the bond-polarizability model and a good agreement with experimental spectra was found. We confirm that the modes associated to the fourfold and threefold rings produce most of the Raman intensity of the D1 and D2 peaks, respectively, in the VV Raman spectra. Modifications of the Raman spectra upon compression are found to be in agreement with experimental data. We show that the modes associated to the fourfold rings still exist upon compression but do not produce a strong Raman intensity, whereas the ones associated to the threefold rings do. This result strongly suggests that the area under the D1 and D2 peaks is not directly proportional to the concentration of small rings in amorphous SiO2.Comment: 21 pages, 8 figures. Phys. Rev. B, in pres

Effect of feeding three lysine to energy diets on growth, body composition and age at puberty in replacement gilts

This study evaluated the effect of diets differing in standard ileal digestible (SID) lysine on lysine intake, growth rate, body composition and age at puberty on maternal line gilts. Crossbred Large White×Landrace gilts (n =641) were fed corn-soybean diets differing in SID lysine concentration (%, g SID lysine:Mcal ME); diets were not isocaloric. Gilts received three grower, finisher diet combinations: low (0.68% lysine grower, 0.52% lysine finisher), medium (0.79% lysine grower, 0.60% lysine finisher) or high (0.90% lysine grower, 0.68% lysine finisher). Grower diets were fed from 100 until 142 days of age, and finisher diets were fed until they reached 220 days of age. Body weight (BW), backfat thickness (BF), and loin depth (LD) were recorded every 28 days. From 160–220 days of age, gilts were exposed daily to vasectomized boars and observed for behavioral estrus. Gilts fed the low lysine diet had lower average daily gain and BW (P \u3c 0.05), but not fat depth:LD ratio. The percentage of gilts that displayed natural estrus by 220 days of age was low but not different among dietary treatments (low 27.7%, medium 31.0% and high 37.7%, respectively; P=0.1201). Gilts fed the high and medium diets reached puberty 10 and 6 days earlier, however, than gilts fed the low lysine diet (P \u3c 0.05). The rate of puberty attainment may have been less because all gilts contracted porcine epidemic diarrhea (PEDv) just as boar exposure was to begin for the first group of gilts. Results from the present study indicate that growth rate and age at puberty can be altered by ad libitum fed diets that differ in SID lysine concentration

Analysis of Spontaneous Reports of Hypoglycemia and Hyperglycemia associated with marketed systemic fluoroquinolones made to the Canadian adverse drug reaction monitoring program

Hypoglycemia, an adverse effect that may develop rapidly and progress to cause potentially serious consequences over a short period of time, is difficult to monitor in both outpatients and inpatients, and may be associated with serious central nervous system sequelae. Four recently published cases of severe acute hypoglycemia with gatifloxacin stimulated a review of the published literature and spontaneous adverse drug reaction reports made in Canada on fluoroquinolone-induced hypoglycemia or hyperglycemia. A search of the English literature for published reports of hypoglycemia associated with ciprofloxacin, gatifloxacin, levofloxacin, and moxifloxacin revealed 2 published case reports of hypoglycemia attributed to the potential drug–drug interaction of an oral hypoglycemic agent with ciprofloxacin; 4 such reports with gatifloxacin; and no reports with either levofloxacin or moxifloxacin. All spontaneously reported adverse drug reactions made to the Canadian Adverse Drug Reaction Monitoring Program (CADRMP) listed under the Metabolic and Nutritional Disorders category for the 3 marketed respiratory fluoroquinolones (gatifloxacin, levofloxacin, and moxifloxacin) were then obtained. Altogether, 25 (93%) of 27 reports in this category were due to either hypoglycemia or hyperglycemia with gatifloxacin; 4 (11%) of 35 reports, with levofloxacin; and 1 (10%) of 10 reports, with moxifloxacin. The number of case reports for hypoglycemia (x2 = 24; p < 0.001), hyperglycemia (x2 = 8; p < 0.05), and total (hypoglycemia, hyperglycemia, and both hypoglycemia and hyperglycemia) (x2 = 46; p < 0.001) was significantly higher for gatifloxacin than for either levofloxacin or moxifloxacin. The CADRMP reports for hypoglycemia or hyperglycemia with the respiratory fluoroquinolones may have identified a safety signal for gatifloxacin. A systematic analysis to determine causality, risk factors, and incidence of hypoglycemia or hyperglycemia may be warranted