In situ transmission electron microscopy based nanopillar compression is utilized to investigate the mechanical properties of zinc dialkyldithiophosphate (ZDDP) tribological films. Small scale ...testing provides localized insights into the properties of ZDDP films that spatially vary in composition at the nanoscale. Large variations in yield strength, between 0.82 and 4.8 GPa, are measured and correlated with local chemistry changes. Lower density regions of the film that tend to be carbon-rich have lower yield stresses, than higher density regions that tend to be zinc-, iron-, and sulfur-rich. It is hypothesized that the strong compositional dependence in mechanical properties at the nanoscale is an important factor contributing to the efficacy of ZDDP as an antiwear tribological film.
Knowledge of their bulk physical properties often guides selection of appropriate tribological coating materials. However, these properties as well as the microstructure evolve dramatically under the ...extreme conditions imposed during mechanical wear. The dynamic response ultimately governs the material’s wear performance; thus, understanding the dynamic evolution of the system is critical. This work characterizes the change in mechanical properties and microstructure as a function of wear cycles in model MoS2 films using a combination of nanowear testing, transmission electron microscopy, and site-specific nanopillar compression. Notably, mechanical wear enhances the mechanical properties of the MoS2 while simultaneously evolving a microstructure that reduces the coefficient of friction and wear rate. We hypothesize that this self-optimizing behavior underpins the exceptional lubricity and antiwear performance of MoS2.
Eliglustat, an oral substrate reduction therapy, is approved for eligible adults with Gaucher disease type 1. In the Phase 3 ENGAGE trial of previously untreated adults with Gaucher disease type 1, ...eliglustat‐treated patients had statistically significant improvements in organ volumes and hematologic parameters compared with placebo in the 9‐month primary analysis. We report final outcomes by time on eliglustat among all patients who participated in the ENGAGE trial and extension. No patient deteriorated clinically or withdrew due to adverse events; 39/40 patients entered the open‐label extension period and 34/40 (85%) remained in the trial until completion or switching to commercial eliglustat after its approval (2.3–6 years). Clinically meaningful improvements in Gaucher disease manifestations were seen in all patients concomitant with reductions in pathological lipid substrate levels (glucosylceramide and glucosylsphingosine). Among patients with 4.5 years of eliglustat exposure, mean spleen volume decreased by 66% (from 17.1 to 5.8 multiples of normal MN, n = 13), mean liver volume decreased by 23% (from 1.5 to 1.1 MN, n = 13), mean hemoglobin increased 1.4 g/dl (from 11.9 to 13.4 g/dl, n = 12), mean platelet count increased by 87% (from 67.6 to 122.6 × 109/L, n = 12), median chitotriosidase decreased by 82% (from 13 394 to 2312 nmol/h/ml, n = 11), median glucosylceramide decreased by 79% (from 11.5 to 2.4 μg/ml, n = 11), median glucosylsphingosine decreased by 84% (from 518.5 to 72.1 ng/ml, n = 10), and mean spine T‐score increased from −1.07 (osteopenia) to −0.53 (normal) (n = 9). The magnitude of improvement in Gaucher disease manifestations and biomarkers over time was similar among the full trial cohort. Eliglustat was well‐tolerated and led to clinically significant improvements in previously untreated patients with Gaucher disease type 1 during 4.5 years of treatment.
It has been established that bile salts play a role in the regulation of hepatic lipid metabolism. Accordingly, overt signs of steatosis have been observed in mice with reduced bile salt synthesis. ...The aim of this study was to identify the mechanism of hepatic steatosis in mice with bile salt deficiency due to a liver specific disruption of cytochrome P450 reductase.
In this study mice lacking hepatic cytochrome P450 reductase (Hrn) or wild type (WT) mice were fed a diet supplemented with or without either 0.1% cholic acid (CA) or 0.025% obeticholic acid, a specific FXR-agonist.
Feeding a CA-supplemented diet resulted in a significant decrease of plasma ALT in Hrn mice. Histologically, hepatic steatosis ameliorated after CA feeding and this was confirmed by reduced hepatic triglyceride content (115.5±7.3mg/g liver and 47.9±4.6mg/g liver in control- and CA-fed Hrn mice, respectively). The target genes of FXR-signaling were restored to normal levels in Hrn mice when fed cholic acid. VLDL secretion in both control and CA-fed Hrn mice was reduced by 25% compared to that in WT mice. In order to gain insight in the mechanism behind these bile salt effects, the FXR agonist also was administered for 3weeks. This resulted in a similar decrease in liver triglycerides, indicating that the effect seen in bile salt fed Hrn animals is FXR dependent.
In conclusion, steatosis in Hrn mice is ameliorated when mice are fed bile salts. This effect is FXR dependent. Triglyceride accumulation in Hrn liver may partly involve impaired VLDL secretion.
•Bile salt deficient Hrn mice show overt signs of hepatic steatosis.•Hepatic steatosis ameliorates when the bile salt pool is restored.•Reduction of hepatic triglyceride is FXR-dependent.
Property Self-Optimization During Wear of MoS 2 Hao, Rui; Tedstone, Aleksander A; Lewis, David J ...
ACS applied materials & interfaces,
2017-Jan-18, 2017-01-18, Letnik:
9, Številka:
2
Journal Article
Recenzirano
Knowledge of their bulk physical properties often guides selection of appropriate tribological coating materials. However, these properties as well as the microstructure evolve dramatically under the ...extreme conditions imposed during mechanical wear. The dynamic response ultimately governs the material's wear performance; thus, understanding the dynamic evolution of the system is critical. This work characterizes the change in mechanical properties and microstructure as a function of wear cycles in model MoS
films using a combination of nanowear testing, transmission electron microscopy, and site-specific nanopillar compression. Notably, mechanical wear enhances the mechanical properties of the MoS
while simultaneously evolving a microstructure that reduces the coefficient of friction and wear rate. We hypothesize that this self-optimizing behavior underpins the exceptional lubricity and antiwear performance of MoS
.
An aerosol-assisted chemical vapor method leading to iron sulfide scales of varying phases and morphologies by reaction of pipeline steels with sulfur compounds has been developed. This chemical ...vapor reaction methodology is useful for generating model iron sulfide scales pertinent to the interaction of sour crude oil with piplelines used in the oil and gas industry.
Retinoids have previously been shown to be crucial for normal spermatogenesis. The role of retinoic acid receptors has been
studied, but relatively little is known about the function of retinoid X ...receptors (RXRs). To gain more insight in the function
of RXRs during spermatogenesis, the cellular localization of RXRs in the mouse testis was examined using immunohistochemistry
and RNase protection assays. In both normal and vitamin A-deficient (VAD) testes, a strong immune response to an RXRalpha
antibody occurred in Leydig cells, peritubular myoid cells, and A spermatogonia. Weaker signals were found in spermatocytes
and spermatids. In normal testes, an RXRbeta antibody gave a reaction in Leydig cells, and, to a lesser extent, in Sertoli
cells, A spermatogonia, pachytene spermatocytes, and spermatids. In Leydig cells, a cytoplasmatic signal was found in addition
to the nuclear signal. In the VAD testis, only Leydig cells and A spermatogonia were positive, which indicates that RXRbeta
expression may be dependent on the retinoid status. Previous studies have shown RXRgamma mRNA expression in the mouse testis
at a low level. Nevertheless, an RXRgamma antibody caused a strong immune response in interstitial cells and in A spermatogonia,
and a weak signal in pachytene spermatocytes. These immunohistochemical data were supported by the results of RNase protection
assays on mRNA of testicular cell isolations. In conclusion, the different RXRs in the mouse testis have distinct expression
patterns, suggesting that they may have different functions.
Abstract
Eliglustat, an oral substrate reduction therapy, is a first‐line treatment for adults with Gaucher disease type 1 (GD1) who are poor, intermediate, or extensive CYP2D6 metabolizers (>90% of ...patients). In the primary analysis of the Phase 3 ENGAGE trial (NCT00891202), eliglustat treatment for 9 months resulted in significant reductions in spleen and liver volumes and increases in hemoglobin concentration and platelet count compared with placebo. We report 18‐month outcomes of patients who entered the trial extension period, in which all patients received eliglustat. Of 40 trial patients, 39 entered the extension period, and 38 completed 18 months. Absolute values and percent change over time were determined for spleen and liver volume, hemoglobin concentration, platelet count, bone mineral density, bone marrow burden, and Gaucher disease biomarkers. For patients randomized to eliglustat in the double‐blind period, continuing treatment with eliglustat for 9 more months resulted in incremental improvement of all disease parameters. For patients randomized to placebo in the double‐blind period, eliglustat treatment during the 9‐month, open‐label period resulted in significant decrease of spleen and liver volumes and significant increase of hemoglobin and platelets, with a similar rate of change to patients who had received eliglustat in the double‐blind period. Eliglustat treatment was also associated with improvement in bone marrow burden score, bone mineral density, and established biomarkers of Gaucher disease, including reduction of the bioactive lipid, glucosylsphingosine. These findings underscore the efficacy of eliglustat in treatment‐naïve patients. Eliglustat was well‐tolerated, and there were no new safety concerns with longer‐term exposure.
The expression of carbamoylphosphate synthetase-I (CPS), the first and rate-determining enzyme of the urea cycle, is regulated at the transcriptional level by glucocorticoids and glucagon, the latter ...acting via cyclic AMP (cAMP). The hormonal response is mediated by a distal enhancer located 6.3 kb upstream of the transcription-start site. Within this enhancer, a cAMP-response unit (CRU) is responsible for mediating cAMP-dependent transcriptional activity. The CPS CRU contains binding sites for cAMP-response element (CRE)-binding protein (CRE-BP), forkhead box A (FoxA), CCAAT/enhancer-binding protein (C/EBP), and an unidentified protein P1. To gain insight in the protein–DNA interactions that activate the CPS CRU in living cells, we have employed in vivo footprinting assays. Comparison of the fibroblast cell line Rat-1 and the hepatoma cell lines FTO-2B and WT-8 showed that FoxA binds the CPS CRU constitutively in CPS-expressing cells only. Comparison of FTO-2B and WT-8 hepatoma cells, which only differ in cAMP responsiveness, demonstrated that the binding of the other transcription factors is dependent on cAMP-dependent protein kinase (PKA) activity. Finally, we observed a footprint between the CRE and the P1-binding site in the in vivo footprint assay that was not detectable by in vitro footprint assays, implying a major change in CRU-associated chromatin conformation upon CRU activation. These findings indicate that activation of the CRU is initiated in a tissue-specific manner by the binding of FoxA. When cellular cAMP and glucocorticoid levels increase, CRE-BP becomes activated, allowing the binding of the remaining transcription factors and the transactivation of the CPS promoter.
Left ventricular assist device (LVAD) support is associated with coagulopathy, bleeding, increased blood transfusion, and increased anti-HLA antibody production. Increased anti-HLA antibody ...production is associated with early transplant rejection, transplant coronary artery disease (CAD), and decreased post-transplant survival rates. We asked whether bridging to transplantation with an LVAD increases the risk of transplant CAD.
We reviewed data for all adults (>18 years old) who underwent heart transplantation at our institution between 1988 and 2000. After exclusion of transplant recipients who survived <3 years, we divided the remaining cohort into 2 groups: those bridged to transplantation with LVADs (mean duration of support, 149 +/- 107 days, n = 29) and those in United Network for Organ Sharing Status 1 bridged to transplantation without LVADs (controls, n = 86). We compared groups in terms of disease cause, age, sex, donor age, panel-reactive antibody testing, crossmatching, pre- and post-transplant cholesterol concentrations, diagnosis of diabetes mellitus or treated hypertension, infections, calcium channel blocker use, transplant rejection, ischemic time, cytomegalovirus infection, pre-transplant transfusion, and incidence of transplant CAD (defined as any coronary lesion identified by coronary angiography). We considered p < 0.05 to be significant.
The bridged and control groups were similar in all respects except mean ischemic time (217 +/- 58 minutes vs 179 +/- 67 minutes, p = 0.007), post-transplant cholesterol concentration (212 +/- 55 mg/dl vs 171 +/- 66 mg/dl, p = 0.007), and pre-transplant transfusion incidence (100% vs 22%, p < 0.001). The incidence of transplant CAD was similar in both groups during a 3-year follow-up period (28% vs 17%, p = 0.238) and during total follow-up (34% vs 35%, p = 0.969). Multivariate logistic regression analysis identified cholesterol concentration at 1 year after transplantation as a significant predictor of CAD at 3 years after heart transplantation (p = 0.0029, odds ratio = 0.984).
Bridging to transplantation with an LVAD does not increase the risk of transplant CAD. Nevertheless, aggressive prophylactic therapy to minimize potential risk factors for transplant CAD, such as increased cholesterol concentration, is warranted in all transplant recipients.
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