Notch2 Signaling Sensitizes Endothelial Cells to Apoptosis by Negatively Regulating the Key Protective Molecule Survivin

BACKGROUND: Notch signaling pathway controls key functions in vascular and endothelial cells (ECs) where Notch4 plays a major role. However, little is known about the contribution of other Notch receptors. This study investigated regulation of Notch2 and further examined its implication in EC dysfunction. METHODOLOGY/PRINCIPAL FINDINGS: Here, we provide evidence for a novel link between Notch and TNF signaling, where Notch2 is upregulated and activated in response to TNF. Forced expression of Notch2 intracellular domain in cultured ECs promotes apoptosis and allows the significant downregulation of several cell-death-related transcripts in a dose-dependent manner. In particular, activation of Notch2 led to a rapid decrease in survivin mRNA and protein expression, while survivin upregulation was obtained by the selective knockdown of Notch2 in ECs, indicating that survivin expression is controlled at the Notch level. Moreover, Notch2 silencing and ectopic expression of survivin, but not XIAP or Bcl2, rescued ECs from TNF and Notch2-mediated apoptosis, respectively. CONCLUSIONS/SIGNIFICANCE: In conclusion, TNF signaling activates Notch2 that sensitizes ECs to apoptosis via modulation of the key apoptosis regulator survivin. Overall, our findings also indicate that specific Notch receptors control distinct functions in vascular cells and inflammatory cytokines contribute to this specificity

Pitavastatin Reduces Inflammation in Atherosclerotic Plaques in Apolipoprotein E-Deficient Mice with Late Stage Renal Disease

Objectives: Chronic renal disease (CRD) accelerates atherosclerosis and cardiovascular calcification. Statins reduce low-density lipoprotein-cholesterol levels in patients with CRD, however, the benefits of statins on cardiovascular disease in CRD remain unclear. This study has determined the effects of pitavastatin, the newest statin, on arterial inflammation and calcification in atherogenic mice with CRD. Methods and Results: CRD was induced by 5/6 nephrectomy in cholesterol-fed apolipoprotein E-deficient mice. Mice were randomized into three groups: control mice, CRD mice, and CRD mice treated with pitavastatin. Ultrasonography showed that pitavastatin treatment significantly attenuated luminal stenosis in brachiocephalic arteries of CRD mice. Near-infrared molecular imaging and correlative Mac3 immunostaining demonstrated a significant reduction in macrophage accumulation in pitavastatin-treated CRD mice. Pitavastatin treatment reduced levels of osteopontin in plasma and atherosclerotic lesions in CRD mice, but did not produce a significant reduction in calcification in atherosclerotic plaques as assesses by histology. CRD mice had significantly higher levels of phosphate in plasma than did control mice, which did not change by pitavastatin. In vitro, pitavastatin suppressed the expression of osteopontin in peritoneal macrophages stimulated with phosphate or calcium/phosphate in concentrations similar to those found in human patients with CRD. Conclusion: Our study provides in vivo evidence that pitavastatin reduces inflammation within atherosclerotic lesions in CRD mice

Effect of an 18-Month Meditation Training on Regional Brain Volume and Perfusion in Older Adults: The Age-Well Randomized Clinical Trial.

peer reviewedImportance: No lifestyle-based randomized clinical trial directly targets psychoaffective risk factors of dementia. Meditation practices recently emerged as a promising mental training exercise to foster brain health and reduce dementia risk. Objective: To investigate the effects of meditation training on brain integrity in older adults. Design, Setting, and Participants: Age-Well was a randomized, controlled superiority trial with blinded end point assessment. Community-dwelling cognitively unimpaired adults 65 years and older were enrolled between November 24, 2016, and March 5, 2018, in France. Participants were randomly assigned (1:1:1) to (1) an 18-month meditation-based training, (2) a structurally matched non-native language (English) training, or (3) no intervention arm. Analysis took place between December 2020 and October 2021. Interventions: Meditation and non-native language training included 2-hour weekly group sessions, practice of 20 minutes or longer daily at home, and 1-day intensive practices. Main Outcomes and Measures: Primary outcomes included volume and perfusion of anterior cingulate cortex (ACC) and insula. Main secondary outcomes included a global composite score capturing metacognitive, prosocial, and self-regulatory capacities and constituent subscores. Results: Among 137 participants (mean [SD] age, 69.4 [3.8] years; 83 [60.6%] female; 54 [39.4%] male) assigned to the meditation (n = 45), non-native language training (n = 46), or no intervention (n = 46) groups, all but 1 completed the trial. There were no differences in volume changes of ACC (0.01 [98.75% CI, -0.02 to 0.05]; P = .36) or insula (0.01 [98.75% CI, -0.02 to 0.03]; P = .58) between meditation and no intervention or non-native language training groups, respectively. Differences in perfusion changes did not reach statistical significance for meditation compared with no intervention in ACC (0.02 [98.75% CI, -0.01 to 0.05]; P = .06) or compared with non-native language training in insula (0.02 [98.75% CI, -0.01 to 0.05]; P = .09). Meditation was superior to non-native language training on 18-month changes in a global composite score capturing attention regulation, socioemotional, and self-knowledge capacities (Cohen d, 0.52 [95% CI, 0.19-0.85]; P = .002). Conclusions and Relevance: The study findings confirm the feasibility of meditation and non-native language training in elderly individuals, with high adherence and very low attrition. Findings also show positive behavioral effects of meditation that were not reflected on volume, and not significantly on perfusion, of target brain areas. Trial Registration: ClinicalTrials.gov Identifier: NCT02977819

The rheological properties of silated hydroxypropylmethylcellulose tissue engineering matrices

International audienceThis paper describes the rheological properties of silated hydroxypropylmethylcellulose (HPMC-Si) used in biomaterials domain as a three-dimensional synthetic matrix for tissue engineering. The HPMC-Si is an HPMC grafted with 3-glycidoxypropyltrimethoxysilane (GPTMS). HPMC and HPMC-Si were studied. It is shown that although silanization reduces the hydrodynamic volume in dilute solution, it does not affect significantly the rheological behavior of the concentrated solutions. The HPMC-Si viscous solution (pH 12.8) cross-links by decreasing the pH using an acid buffer, since HPMC-Si solution transforms into an elastic state. The kinetics of cross-linking and final elastic properties is influenced by several parameters such as polymer concentration, pH and temperature. pH and temperature play an important role in the silanol condensation, mainly responsible for network formation. The study of the gelation process revealed the dependence of the final concentration of HPMC-Si hydrogel on cross-linking kinetics and viscoelastic properties. The percolation theory was applied to determine gel point and to discuss the dependence of storage (G') and loss (G'') moduli on frequency. Results showed that both G' and G'' exhibit a power-law behavior with an exponent (0.68) which extends over the entire frequency range. This method is the only one to characterize the time where a liquid viscous phase shifts to hydrogel with elastic properties. In this case it was about 23 min for a final pH of 7.4

The True Nature of Tricalcium Phosphate Used as Food Additive (E341(iii))

Tricalcium phosphate (TCP) is a food additive, labeled E341(iii), used in powdered food preparation, such as baby formula. In the United States, calcium phosphate nano-objects were identified in baby formula extractions. Our goal is to determine whether the TCP food additive, as is used in Europe, can be classified as a nanomaterial. The physicochemical properties of TCP were characterized. Three different samples (from a chemical company and two manufacturers) were thoroughly characterized according to the recommendations of the European Food Safety Authority. A commercial TCP food additive was identified as actually being hydroxyapatite (HA). It presents itself in the form of particles of different shapes (either needle-like, rod, or pseudo-spherical), which were demonstrated in this paper to be of a nanometric dimension: E341(iii) is thus a nanomaterial. In water, HA particles sediment rapidly as agglomerates or aggregates over a pH of 6 and are progressively dissolved in acidic media (pH < 5) until the complete dissolution at a pH of 2. Consequently, since TCP may be considered as a nanomaterial on the European market, it raises the question of its potential persistency in the gastrointestinal tract

Effects of pH and Ca/P molar ratio on the quantity and crystalline structure of calcium phosphates obtained from aqueous solutions

 – Milk and dairy products contain large amounts of calcium phosphate salts that can precipitate. The chemical composition and the crystalline structure of the calcium phosphate precipitates that are formed in dairy industry depend on the physico-chemical conditions, particularly, pH and mineral composition. The objective of this study was to determine, using mineral solutions, the effects of pH and of the concentrations of calcium and phosphate on the quantity and crystalline structure of calcium phosphate precipitates. Experiments were carried out at 20 °C with 20.00 mmol·L−1 phosphate and three Ca/P molar ratios (1.00, 1.50 and 2.00). The initial pH (5.50, 6.70, 7.50, 8.50 and 9.50) were drifting or kept constant during a reaction time of 3 h. After filtration of the suspensions, the mineral compositions of filtrates were quantified. The lyophilized precipitates were characterized using X-ray diffraction, infrared spectroscopy and scanning electron microscopy techniques. At drifting pH (final pH values were between 4.6 and 6.0), the mineral analyses showed that the Ca/P ratio did not influence the amounts of precipitated calcium and phosphate. The analyses of precipitates revealed the formation of brushite as the main crystalline phase. At constant pH, the mineral analyses showed that the Ca/P ratio strongly influenced the precipitation efficiency of calcium phosphate. The analyses of precipitates revealed the formation of poorly crystallized calcium-deficient apatites. A decrease of crystallinity with an increase in initial pH was observed. In conclusion, pH can be a key factor to control the quantity and crystalline structure of calcium phosphates obtained by precipitation. This factor should be considered for the recovery of calcium phosphates from dairy co-products. pH is also important in the fouling phenomena of membranes and heat exchangers caused by calcium phosphate precipitation

The effect of chain microstructure on electrochemical and spectroelectrochemical properties of fluorenone–dialkyl bithiophene alternate copolymers

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Physicochemical characterisation of calcium phosphatesprepared from milk ultrafiltrates: Effect of the mineralcomposition

This study deals with the precipitation of calcium phosphate in permeates removed from milks at differentpH (6.7, 5.2 and 4.6). An overall high yield of precipitation of calcium and phosphate (70–80%, respectively)was obtained for all precipitates with Ca⁄P molar ratios close to 1.5. The suspended milk-derivedcalcium phosphate (MDCP) precipitates had 8–14 lm size and )14 to )28 mV zeta potential. The driedMDCP precipitates were identified as amorphous calcium phosphate (ACP), stable over 18 months ofstorage at room temperature

Polarized Raman spectra of brushite (CaHPO 4 .2H 2 O) crystal. Investigation of the phosphate stretching modes, study of the LOTO splitting

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Preparation and spectroelectrochemical behaviour of a new alternate copolymer of 3,3′-di-n-octyl-2,2′-bithiophene and fluoren-9-one

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