Dietary Silicon Deficiency Does Not Exacerbate Diet-Induced Fatty Lesions in Female ApoE Knockout Mice.

BACKGROUND: Dietary silicon has been positively linked with vascular health and protection against atherosclerotic plaque formation, but the mechanism of action is unclear. OBJECTIVES: We investigated the effect of dietary silicon on 1) serum and aorta silicon concentrations, 2) the development of aortic lesions and serum lipid concentrations, and 3) the structural and biomechanic properties of the aorta. METHODS: Two studies, of the same design, were conducted to address the above objectives. Female mice, lacking the apolipoprotein E (apoE) gene, and therefore susceptible to atherosclerosis, were separated into 3 groups of 10-15 mice, each exposed to a high-fat diet (21% wt milk fat and 1.5% wt cholesterol) but with differing concentrations of dietary silicon, namely: silicon-deprived (-Si; <3-μg silicon/g feed), silicon-replete in feed (+Si-feed; 100-μg silicon/g feed), and silicon-replete in drinking water (+Si-water; 115-μg silicon/mL) for 15-19 wk. Silicon supplementation was in the form of sodium metasilicate (feed) or monomethylsilanetriol (drinking water). RESULTS: The serum silicon concentration in the -Si group was significantly lower than in the +Si-feed (by up to 78%; P < 0.003) and the +Si-water (by up to 84%; P < 0.006) groups. The aorta silicon concentration was also lower in the -Si group than in the +Si-feed group (by 65%; P = 0.025), but not compared with the +Si-water group. There were no differences in serum and aorta silicon concentrations between the silicon-replete groups. Body weights, tissue wet weights at necropsy, and structural, biomechanic, and morphologic properties of the aorta were not affected by dietary silicon; nor were the development of fatty lesions and serum lipid concentrations. CONCLUSIONS: These findings suggest that dietary silicon has no effect on atherosclerosis development and vascular health in the apoE mouse model of diet-induced atherosclerosis, contrary to the reported findings in the cholesterol-fed rabbit model

Complement-Mediated Virus Infectivity Neutralisation by HLA Antibodies Is Associated with Sterilising Immunity to SIV Challenge in the Macaque Model for HIV/AIDS.

Sterilising immunity is a desired outcome for vaccination against human immunodeficiency virus (HIV) and has been observed in the macaque model using inactivated simian immunodeficiency virus (SIV). This protection was attributed to antibodies specific for cell proteins including human leucocyte antigens (HLA) class I and II incorporated into virions during vaccine and challenge virus preparation. We show here, using HLA bead arrays, that vaccinated macaques protected from virus challenge had higher serum antibody reactivity compared with non-protected animals. Moreover, reactivity was shown to be directed against HLA framework determinants. Previous studies failed to correlate serum antibody mediated virus neutralisation with protection and were confounded by cytotoxic effects. Using a virus entry assay based on TZM-bl cells we now report that, in the presence of complement, serum antibody titres that neutralise virus infectivity were higher in protected animals. We propose that complement-augmented virus neutralisation is a key factor in inducing sterilising immunity and may be difficult to achieve with HIV/SIV Env-based vaccines. Understanding how to overcome the apparent block of inactivated SIV vaccines to elicit anti-envelope protein antibodies that effectively engage the complement system could enable novel anti-HIV antibody vaccines that induce potent, virolytic serological response to be developed

Dietary Silicon Deficiency Does Not Exacerbate Diet-Induced Fatty Lesions in Female ApoE Knockout Mice.

BACKGROUND: Dietary silicon has been positively linked with vascular health and protection against atherosclerotic plaque formation, but the mechanism of action is unclear. OBJECTIVES: We investigated the effect of dietary silicon on 1) serum and aorta silicon concentrations, 2) the development of aortic lesions and serum lipid concentrations, and 3) the structural and biomechanic properties of the aorta. METHODS: Two studies, of the same design, were conducted to address the above objectives. Female mice, lacking the apolipoprotein E (apoE) gene, and therefore susceptible to atherosclerosis, were separated into 3 groups of 10-15 mice, each exposed to a high-fat diet (21% wt milk fat and 1.5% wt cholesterol) but with differing concentrations of dietary silicon, namely: silicon-deprived (-Si; <3-μg silicon/g feed), silicon-replete in feed (+Si-feed; 100-μg silicon/g feed), and silicon-replete in drinking water (+Si-water; 115-μg silicon/mL) for 15-19 wk. Silicon supplementation was in the form of sodium metasilicate (feed) or monomethylsilanetriol (drinking water). RESULTS: The serum silicon concentration in the -Si group was significantly lower than in the +Si-feed (by up to 78%; P < 0.003) and the +Si-water (by up to 84%; P < 0.006) groups. The aorta silicon concentration was also lower in the -Si group than in the +Si-feed group (by 65%; P = 0.025), but not compared with the +Si-water group. There were no differences in serum and aorta silicon concentrations between the silicon-replete groups. Body weights, tissue wet weights at necropsy, and structural, biomechanic, and morphologic properties of the aorta were not affected by dietary silicon; nor were the development of fatty lesions and serum lipid concentrations. CONCLUSIONS: These findings suggest that dietary silicon has no effect on atherosclerosis development and vascular health in the apoE mouse model of diet-induced atherosclerosis, contrary to the reported findings in the cholesterol-fed rabbit model

Geogenic and atmospheric sources for volatile organic compounds in fumarolic emissions from Mt. Etna and Vulcano Island (Sicily, Italy)

In this paper, fluid source(s) and processes controlling the chemical composition of volatile organic compounds (VOCs) in gas discharges from Mt. Etna and Vulcano Island(Sicily, Italy) were investigated. The main composition of the Etnean and Volcano gas emissions is produced by mixing, to various degrees, of magmatic and hydrothermal components. VOCs are dominated by alkanes, alkenes and aromatics, with minor, though significant, concentrations of O-, S- and Cl(F)-substituted compounds. The main mechanism for the production of alkanes is likely related to pyrolysis of organic-matterbearing sediments that interact with the ascending magmatic fluids. Alkanes are then converted to alkene and aromatic compounds via catalytic reactions (dehydrogenation and dehydroaromatization, respectively). Nevertheless, an abiogenic origin for the light hydrocarbons cannot be ruled out. Oxidative processes of hydrocarbons at relatively high temperatures and oxidizing conditions, typical of these volcanic-hydrothermal fluids, may explain the production of alcohols, esters, aldehydes, as well as O- and S-bearing heterocycles. By comparing the concentrations of hydrochlorofluorocarbons (HCFCs) in the fumarolic discharges with respect to those of background air, it is possible to highlight that they have a geogenic origin likely due to halogenation of both methane and alkenes. Finally, chlorofluorocarbon (CFC) abundances appear to be consistent with background air, although the strong air contamination that affects the Mt. Etna fumaroles may mask a possible geogenic contribution for these compounds. On the other hand, no CFCs were detected in the Vulcano gases, which are characterized by low air contribution. Nevertheless, a geogenic source for these compounds cannot be excluded on the basis of the present data

Atmospheric implications of studies of Central American volcanic eruption clouds

During February 1978 a group of scientists from the National Center for Atmospheric Research, several colleges and universities, the U.S. Geological Survey, and NASA used a specially equipped Beech Queen Air aircraft to make 11 sampling flights in Guatemala through the eruption clouds from the volcanoes Pacaya, Fuego, and Santiguito. Measurements were made of SO42−, SO2, HCl, HF, and 11 cations that were in water-soluble form, on samples collected by a specially designed filter pack. Particle size distributions were obtained with a piezoelectric cascade impactor, and the particles were identified by energy dispersive X ray analysis. Evacuated canisters were flown to obtain samples for gas Chromatographic analysis. Some of the conclusions reached are that since most of the sulfur was found to be in the form of SO2, the H2SO4 droplets resulting from major explosive eruptions must largely result from the reaction of SO2 with OH, at the same time depleting the atmosphere of OH; the volume concentration ratio [SO2]/[HCl] always somewhat exceeded unity; and the amount of fine ash remaining in the stratosphere for long periods of time may depend on the crystallinity of the magma. Correlation spectrometry showed that each volcano was emitting 300–1500 metric tons of SO2 per day

JAK-STAT inhibition impairs K-RAS-driven lung adenocarcinoma progression

Oncogenic KRAS has been difficult to target and currently there is no KRASbased targeted therapy available for patients suffering from KRASdriven lung adenocarcinoma (AC). Alternatively, targeting KRASdownstream effectors, KRAScooperating signaling pathways or cancer hallmarks, such as tumorpromoting inflammation, has been shown to be a promising therapeutic strategy. Since the JAKSTAT pathway is considered to be a central player in inflammationmediated tumorigenesis, we investigated here the implication of JAKSTAT signaling and the therapeutic potential of JAK1/2 inhibition in KRASdriven lung AC. Our data showed that JAK1 and JAK2 are activated in human lung AC and that increased activation of JAKSTAT signaling correlated with disease progression and KRAS activity in human lung AC. Accordingly, administration of the JAK1/2 selective tyrosine kinase inhibitor ruxolitinib reduced proliferation of tumor cells and effectively reduced tumor progression in immunodeficient and immunocompetent mouse models of KRASdriven lung AC. Notably, JAK1/2 inhibition led to the establishment of an antitumorigenic tumor microenvironment, characterized by decreased levels of tumorpromoting chemokines and cytokines and reduced numbers of infiltrating myeloid derived suppressor cells, thereby impairing tumor growth. Taken together, we identified JAK1/2 inhibition as promising therapy for KRASdriven lung AC.(VLID)510233

Renal sympathetic denervation restores aortic distensibility in patients with resistant hypertension: data from a multi-center trial

Renal sympathetic denervation (RDN) is under investigation as a treatment option in patients with resistant hypertension (RH). Determinants of arterial compliance may, however, help to predict the BP response to therapy. Aortic distensibility (AD) is a well-established parameter of aortic stiffness and can reliably be obtained by CMR. This analysis sought to investigate the effects of RDN on AD and to assess the predictive value of pre-treatment AD for BP changes. We analyzed data of 65 patients with RH included in a multicenter trial. RDN was performed in all participants. A standardized CMR protocol was utilized at baseline and at 6-month follow-up. AD was determined as the change in cross-sectional aortic area per unit change in BP. Office BP decreased significantly from 173/92 ± 24/16 mmHg at baseline to 151/85 ± 24/17 mmHg (p < 0.001) 6 months after RDN. Maximum aortic areas increased from 604.7 ± 157.7 to 621.1 ± 157.3 mm2 (p = 0.011). AD improved significantly by 33% from 1.52 ± 0.82 to 2.02 ± 0.93 × 10-3 mmHg-1 (p < 0.001). Increase of AD at follow-up was significantly more pronounced in younger patients (p = 0.005) and responders to RDN (p = 0.002). Patients with high-baseline AD were significantly younger (61.4 ± 10.1 vs. 67.1 ± 8.4 years, p = 0.022). However, there was no significant correlation of baseline AD to response to RDN. AD is improved after RDN across all age groups. Importantly, these improvements appear to be unrelated to observed BP changes, suggesting that RDN may have direct effects on the central vasculature

HIV gp41 Engages gC1qR on CD4+ T Cells to Induce the Expression of an NK Ligand through the PIP3/H2O2 Pathway

CD4+ T cell loss is central to HIV pathogenesis. In the initial weeks post-infection, the great majority of dying cells are uninfected CD4+ T cells. We previously showed that the 3S motif of HIV-1 gp41 induces surface expression of NKp44L, a cellular ligand for an activating NK receptor, on uninfected bystander CD4+ T cells, rendering them susceptible to autologous NK killing. However, the mechanism of the 3S mediated NKp44L surface expression on CD4+ T cells remains unknown. Here, using immunoprecipitation, ELISA and blocking antibodies, we demonstrate that the 3S motif of HIV-1 gp41 binds to gC1qR on CD4+ T cells. We also show that the 3S peptide and two endogenous gC1qR ligands, C1q and HK, each trigger the translocation of pre-existing NKp44L molecules through a signaling cascade that involves sequential activation of PI3K, NADPH oxidase and p190 RhoGAP, and TC10 inactivation. The involvement of PI3K and NADPH oxidase derives from 2D PAGE experiments and the use of PIP3 and H2O2 as well as small molecule inhibitors to respectively induce and inhibit NKp44L surface expression. Using plasmid encoding wild type or mutated form of p190 RhoGAP, we show that 3S mediated NKp44L surface expression on CD4+ T cells is dependent on p190 RhoGAP. Finally, the role of TC10 in NKp44L surface induction was demonstrated by measuring Rho protein activity following 3S stimulation and using RNA interference. Thus, our results identify gC1qR as a new receptor of HIV-gp41 and demonstrate the signaling cascade it triggers. These findings identify potential mechanisms that new therapeutic strategies could use to prevent the CD4+ T cell depletion during HIV infection and provide further evidence of a detrimental role played by NK cells in CD4+ T cell depletion during HIV-1 infection

Super-enhancer-based identification of a BATF3/IL-2R-module reveals vulnerabilities in anaplastic large cell lymphoma.

Anaplastic large cell lymphoma (ALCL), an aggressive CD30-positive T-cell lymphoma, comprises systemic anaplastic lymphoma kinase (ALK)-positive, and ALK-negative, primary cutaneous and breast implant-associated ALCL. Prognosis of some ALCL subgroups is still unsatisfactory, and already in second line effective treatment options are lacking. To identify genes defining ALCL cell state and dependencies, we here characterize super-enhancer regions by genome-wide H3K27ac ChIP-seq. In addition to known ALCL key regulators, the AP-1-member BATF3 and IL-2 receptor (IL2R)-components are among the top hits. Specific and high-level IL2R expression in ALCL correlates with BATF3 expression. Confirming a regulatory link, IL-2R-expression decreases following BATF3 knockout, and BATF3 is recruited to IL2R regulatory regions. Functionally, IL-2, IL-15 and Neo-2/15, a hyper-stable IL-2/IL-15 mimic, accelerate ALCL growth and activate STAT1, STAT5 and ERK1/2. In line, strong IL-2Rα-expression in ALCL patients is linked to more aggressive clinical presentation. Finally, an IL-2Rα-targeting antibody-drug conjugate efficiently kills ALCL cells in vitro and in vivo. Our results highlight the importance of the BATF3/IL-2R-module for ALCL biology and identify IL-2Rα-targeting as a promising treatment strategy for ALCL