Extracellular polymeric substances (EPS) are expected to be an important source for the formation of mineral-organic associations in soil. Because such formations affect the composition of mobile and ...immobile organic matter as well as the reactivity of minerals, we investigated the composition of EPS before and after adsorption to goethite. Raman measurements on EPS extracted from Bacillus subtilis distinguished four fractions rich in proteins, polysaccharides, lipids, or lipids and proteins. Scanning transmission X-ray microscopy identified three different EPS-fractions that varied in their composition in proteins, nonaromatic proteins, and polysaccharides. Reaction of EPS with goethite led to a preferential adsorption of lipids and proteins. The organic coverage was heterogeneous, consisting of ∼100 × 200 nm large patches of either lipid-rich or protein-rich material. Nanoscale secondary ion mass spectrometry showed a strong S enrichment in aggregates of ∼400 nm in the goethite adsorbed EPS. From our simplified model system, we learned that only a small portion (<10%) of EPS was immobilized via adsorption to goethite. This fraction formed a coating of subμm spaced protein-rich and lipid-rich domains, i.e., of two materials which will strongly differ in their reactive sites. This will finally affect further adsorption, the particle mobility and eventually also colloidal stability.
1 Vascular Signalling Group, Institut für Kardiovaskuläre Physiologie, Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany; 2 Department of Biochemistry, University of Texas Southwestern ...Medical Center, Dallas, Texas
Submitted 28 January 2008
; accepted in final form 9 September 2008
Cytochrome P -450 (CYP) epoxygenases metabolize arachidonic acid to epoxyeicosatrienoic acid (EET) regioisomers, which activate several signaling pathways to promote endothelial cell proliferation, migration, and angiogenesis. Since vascular endothelial growth factor (VEGF) plays a key role in angiogenesis, we assessed a possible role of EETs in the VEGF-activated signal transduction cascade. Stimulation with VEGF increased CYP2C promoter activity in endothelial cells and enhanced CYP2C8 mRNA and protein expression resulting in increased intracellular EET levels. VEGF-induced endothelial cell tube formation was inhibited by the EET antagonist 14,15-epoxyeicosa-5( Z )-enoicacid (14,15-EEZE), which did not affect the VEGF-induced phosphorylation of its receptor or basic fibroblast growth factor (bFGF)-stimulated tube formation. Moreover, VEGF-stimulated endothelial cell sprouting in a modified spheroid assay was reduced by CYP2C antisense oligonucleotides. Mechanistically, VEGF stimulated the phosphorylation of the AMP-activated protein kinase (AMPK), which has also been linked to CYP induction, and the overexpression of a constitutively active AMPK mutant increased CYP2C expression. On the other hand, a dominant-negative AMPK mutant prevented the VEGF-induced increase in CYP2C RNA and protein expression in human endothelial cells. In vivo (Matrigel plug assay) in mice, endothelial cells were recruited into VEGF-impregnated plugs; an effect that was sensitive to 14,15-EEZE and the inclusion of small interfering RNA directed against the AMPK. The EET antagonist did not affect responses observed in plugs containing bFGF. Taken together, our data indicate that CYP2C-derived EETs participate as second messengers in the angiogenic response initiated by VEGF and that preventing the increase in CYP expression curtails the angiogenic response to VEGF.
cytochrome P -450; matrigel plug assay
Address for reprint requests and other correspondence: I. Fleming, Vascular Signalling Group, Institut für Kardiovaskuläre Physiologie, Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany (e-mail: fleming{at}em.uni-frankfurt.de )
The microstructural and chemical evolution after different processing steps of Ta-containing NiCoCrAlY bond coats (BC) sprayed by high velocity oxy-fuel on Ni-base superalloy (SA) substrates, ...top-coated with 7YSZ and furnace cycled at 1100 °C focusing along the BC/SA interfaces is presented. Three superalloys were selected considering their Ta content relative to that within the BC: a) no Ta in the superalloy composition (IN100) and either b) similar or c) higher Ta content with respect to the BC (M247LC SX and CMSX-4, respectively). The processing conditions were as-sprayed, as-annealed, after EB-PVD deposition of a 7YSZ top coat, and after furnace cyclic tests (1100 °C/120 h). The evolution of chemical composition after the different process steps are presented that include a normalization criteria to a Ni-Al-Cr system, elemental profiles as well as Weibull distribution plots of minor containing elements such as Ti, Ta, Mo, or W at the BC/SA interface. The effect of Ta was activated in some coated substrates by the presence of Ti and C in the superalloy consisting of inward Ta-diffusion, trapping of outward diffusing Ti and the subsequent formation of (Ta, Ti)-rich carbides in the BC avoiding possible segregation effects as titanium oxide in the oxide scale.
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•NiCoCrAlYTa coatings were deposited by HVOF on IN100, M247LC SX, and CMSX-4.•Elemental diffusion along BC/SA was investigated after different processing stages.•Coating microstructure under cyclic tests is affected by SA composition.•A gradient of carbides composition is observed due to Ti from the SA trapped by Ta.•Composition of (Ta, Ti)-carbides within the BC on IN100 and M247LC SX are reported.
In this report, we present the results of a multicenter study to test analytic and diagnostic performance of soluble forms of amyloid precursor proteins alpha and beta (sAPP alpha and sAPP beta) in ...the cerebrospinal fluid (CSF) of patients with different forms of dementing conditions. CSF samples were collected from 188 patients with early dementia (mini-mental state examination >or=20 in majority of cases) and mild cognitive impairment (MCI) in 12 gerontopsychiatric centers, and the clinical diagnoses were supported by neurochemical dementia diagnostic (NDD) tools: CSF amyloid beta peptides, Tau and phospho-Tau. sAPP alpha and sAPP beta were measured with multiplexing method based on electrochemiluminescence. sAPP alpha and sAPP beta CSF concentrations correlated with each other with very high correlation ratio (R=0.96, P<0.001). We observed highly significantly increased sAPP alpha and sAPP beta CSF concentrations in patients with NDD characteristic for Alzheimer's disease (AD) compared to those with NDD negative results. sAPP alpha and sAPP beta highly significantly separated patients with AD, whose diagnosis was supported by NDD findings (sAPP alpha: cutoff, 117.4 ng ml(-1), sensitivity, 68%, specificity, 85%, P<0.001; sAPP beta: cutoff, 181.8 ng ml(-1), sensitivity, 75%, specificity, 85%, P<0.001), from the patients clinically assessed as having other dementias and supported by NDD untypical for AD. We conclude sAPP alpha and sAPP beta might be regarded as novel promising biomarkers supporting the clinical diagnosis of AD.
Body fluids are easily accessible and contain valuable indices for medical diagnosis. Fascinating tools are tumour cells circulating in the peripheral blood of cancer patients. As these cells are ...extremely rare, they constitute a challenge for clinical diagnostics. In this contribution we present the Raman spectroscopic-based identification of different single cells in suspension that are found in peripheral blood of cancer patients including healthy cells like leukocytes and erythrocytes, and tumour cells like leukaemic cells and cells originating from solid tumours. Leukocytes and erythrocytes were isolated from the peripheral blood of healthy donors while myeloid leukaemia cells (OCI-AML3) and breast carcinoma derived cells (MCF-7, BT-20) were obtained from cell cultures. A laser emitting 785 nm light was used for optical trapping the single cells in the laser focus and to excite the Raman spectrum. Support vector machines were applied to develop a supervised classification model with spectra of 1210 cells originating from three different donors and three independent cultivation batches. Distinguishing tumour cells from healthy cells was achieved with a sensitivity of >99.7% and a specificity of >99.5%. In addition, the correct cell types were predicted with an accuracy of approximately 92%.
Mechanical joining technologies are increasingly used in multi-material lightweight constructions and offer opportunities to create versatile joining processes due to their low heat input, robustness ...to metallurgical incompatibilities and various process variants. They can be categorised into technologies which require an auxiliary joining element, or do not require an auxiliary joining element. A typical example for a mechanical joining process with auxiliary joining element is self-piercing riveting. A wide range of processes exist which are not requiring an auxiliary joining element. This allows both point-shaped (e.g., by clinching) and line-shaped (e.g., friction stir welding) joints to be produced. In order to achieve versatile processes, challenges exist in particular in the creation of intervention possibilities in the process and the understanding and handling of materials that are difficult to join, such as fiber reinforced plastics (FRP) or high-strength metals. In addition, predictive capability is required, which in particular requires accurate process simulation. Finally, the processes must be measured non-destructively in order to generate control variables in the process or to investigate the cause-effect relationship. This paper covers the state of the art in scientific research concerning mechanical joining and discusses future challenges on the way to versatile mechanical joining processes.
We investigated relations between amyloid-β (Aβ) status, apolipoprotein E (APOE) ε4, and cognition, with cerebrospinal fluid markers of neurogranin (Ng), neurofilament light (NFL), YKL-40, and total ...tau (T-tau).
We included 770 individuals with normal cognition, mild cognitive impairment, and Alzheimer's disease (AD)-type dementia from the EMIF-AD Multimodal Biomarker Discovery study. We tested the association of Ng, NFL, YKL-40, and T-tau with Aβ status (Aβ− vs. Aβ+), clinical diagnosis APOE ε4 carriership, baseline cognition, and change in cognition.
Ng and T-tau distinguished between Aβ+ from Aβ− individuals in each clinical group, whereas NFL and YKL-40 were associated with Aβ+ in nondemented individuals only. APOE ε4 carriership did not influence NFL, Ng, and YKL-40 in Aβ+ individuals. NFL was the best predictor of cognitive decline in Aβ+ individuals across the cognitive spectrum.
Axonal degeneration, synaptic dysfunction, astroglial activation, and altered tau metabolism are involved already in preclinical AD. NFL may be a useful prognostic marker.
Abstract
Background
Integrase strand transfer inhibitors (InSTIs) are recommended for first-line treatment of persons with human immunodeficiency virus (HIV). We identified risk factors, including ...baseline minor InSTI resistance mutations, for treatment failure of InSTI-based regimens.
Methods
We studied time-to-treatment failure and time to viral suppression among 1419 drug-naive patients in the Swiss HIV Cohort Study. We performed Cox regression models adjusted for demographic factors, baseline HIV RNA/CD4 cell counts, AIDS-defining events, and the type of InSTI. In 646 patients with a baseline genotypic resistance test of the integrase, we studied the impact of minor integrase resistance mutations.
Results
We observed 121 virological failures during 18 447 person-years of follow-up. A baseline viral load ≥100 000 copies/mL (multivariable hazard ratio mHR, 2.2; 95% confidence interval CI, 1.3–3.6) and an AIDS-defining event (mHR, 1.8; 95% CI. 1.1–3.0) were associated with treatment failure. CD4 counts between 200 and 500 cells/µL (mHR, 0.5; 95% CI, .3–.8) and >500 cells/µL (mHR, 0.4; 95% CI, .2–.7) were protective. Time to suppression was shorter in lower viral load strata (mHR, 0.7; 95% CI, .6–.8) and in dolutegravir-based therapy (mHR, 1.2; 95% CI, 1.0–1.4). Minor resistance mutations were found at baseline in 104 of 646 (16%) patients with no effect on treatment outcome.
Conclusions
Factors associated with treatment failure on InSTI-based first-line regimen remained similar to those of older treatments, in particular high viral load and low CD4 counts.
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