There is growing evidence that obesity has deleterious effects on the brain and cognitive function in the elderly population. However, the specific mechanisms through which aging and obesity interact ...to promote cognitive decline remain unclear. To test the hypothesis that aging exacerbates obesity-induced cerebromicrovascular damage and neuroinflammation, we compared young (7 months) and aged (24 months) high fat diet-fed obese C57BL/6 mice. Aging exacerbated obesity-induced systemic inflammation and blood-brain barrier disruption, as indicated by the increased circulating levels of proinflammatory cytokines and increased presence of extravasated immunoglobulin G in the hippocampus, respectively. Obesity-induced blood-brain barrier damage was associated with microglia activation, upregulation of activating Fc-gamma receptors and proinflammatory cytokines, and increased oxidative stress. Treatment of cultured primary microglia with sera derived from aged obese mice resulted in significantly more pronounced microglia activation and oxidative stress, as compared with treatment with young sera. Serum-induced activation and oxidative stress were also exacerbated in primary microglia derived from aged animals. Hippocampal expression of genes involved in regulation of the cellular amyloid precursor protein-dependent signaling pathways, beta-amyloid generation, and the pathogenesis of tauopathy were largely unaffected by obesity in aged mice. Collectively, obesity in aging is associated with a heightened state of systemic inflammation, which exacerbates blood-brain barrier disruption. The resulting neuroinflammation and oxidative stress in the mouse hippocampus likely contribute to the significant cognitive decline observed in aged obese animals.
Context.
The solar telescope connected to HARPS-N has been observing the Sun since the summer of 2015. Such a high-cadence, long-baseline data set is crucial for understanding spurious ...radial-velocity signals induced by our Sun and by the instrument. On the instrumental side, this data set allowed us to detect sub- m s
−1
systematics that needed to be corrected for.
Aims.
The goals of this manuscript are to (i) present a new data reduction software for HARPS-N, (ii) demonstrate the improvement brought by this new software during the first three years of the HARPS-N solar data set, and (iii) release all the obtained solar products, from extracted spectra to precise radial velocities.
Methods.
To correct for the instrumental systematics observed in the data reduced with the current version of the HARPS-N data reduction software (DRS version 3.7), we adapted the newly available ESPRESSO DRS (version 2.2.3) to HARPS-N and developed new optimised recipes for the spectrograph. We then compared the first three years of HARPS-N solar data reduced with the current and new DRS.
Results.
The most significant improvement brought by the new DRS is a strong decrease in the day-to-day radial-velocity scatter, from 1.27 to 1.07 m s
−1
; this is thanks to a more robust method to derive wavelength solutions, but also to the use of calibrations closer in time. The newly derived solar radial-velocities are also better correlated with the chromospheric activity level of the Sun in the long term, with a Pearson correlation coefficient of 0.93 compared to 0.77 before, which is expected from our understanding of stellar signals. Finally, we also discuss how HARPS-N spectral ghosts contaminate the measurement of the calcium activity index, and we present an efficient technique to derive an index free of instrumental systematics.
Conclusions.
This paper presents a new data reduction software for HARPS-N and demonstrates its improvements, mainly in terms of radial-velocity precision, when applied to the first three years of the HARPS-N solar data set. Those newly reduced solar data, representing an unprecedented time series of 34 550 high-resolution spectra and precise radial velocities, are released alongside this paper. Those data are crucial to understand stellar activity signals in solar-type stars further and develop the mitigating techniques that will allow us to detect other Earths.
Epidemiological studies show that obesity has deleterious effects on the brain and cognitive function in the elderly population. However, the specific mechanisms through which aging and obesity ...interact to promote cognitive decline remain unclear. To test the hypothesis that aging exacerbates obesity-induced cerebromicrovascular impairment, we compared young (7 months) and aged (24 months) high-fat diet-fed obese C57BL/6 mice. We found that aging exacerbates the obesity-induced decline in microvascular density both in the hippocampus and in the cortex. The extent of hippocampal microvascular rarefaction and the extent of impairment of hippocampal-dependent cognitive function positively correlate. Aging exacerbates obesity-induced loss of pericyte coverage on cerebral microvessels and alters hippocampal angiogenic gene expression signature, which likely contributes to microvascular rarefaction. Aging also exacerbates obesity-induced oxidative stress and induction of NADPH oxidase and impairs cerebral blood flow responses to whisker stimulation. Collectively, obesity exerts deleterious cerebrovascular effects in aged mice, promoting cerebromicrovascular rarefaction and neurovascular uncoupling. The morphological and functional impairment of the cerebral microvasculature in association with increased blood-brain barrier disruption and neuroinflammation (Tucsek Z, Toth P, Sosnowsk D, et al. Obesity in aging exacerbates blood-brain barrier disruption, neuroinflammation and oxidative stress in the mouse hippocampus: effects on expression of genes involved in beta-amyloid generation and Alzheimer's disease. J Gerontol Biol Med Sci. 2013. In press, PMID: 24269929) likely contribute to obesity-induced cognitive decline in aging.
Spent hops extract (SHE) is a plant extract containing compounds with proven anti-inflammatory and anti-angiogenic activities. However, extract may exert synergic effects compared to its individual ...polyphenol components. Inflammatory diseases of the retina may lead to visual impairment, a reduction of the comfort of life, and even blindness due to the formation of new pathological blood vessels. More effective therapeutic options are being sought. The goal of the present study was to investigate the anti-inflammatory and anti-angiogenic potentials of SHE on human retinal pigment epithelial cells (ARPE-19) stimulated by lipopolysaccharide (LPS) or tumor necrosis factor alpha (TNF-α). The SHE (250 μg/mL) was found to downregulate the gene expression of interleukin 6 (IL-6) to 33% in LPS-triggered cells; it also reduced both matrix metalloproteinase 2 (MMP-2) and 9 (MMP-9) mRNA expression to 13% and 43% respectively, and their activity to 82% (MMP-2) and 57% (MMP-9), compared to TNF-α-stimulated cells. Also, SHE modulated the TNF-α-induced expression of vascular endothelial growth factor (VEGF) and endothelial growth factor receptor 2 (VEGFR2). It is possible that SHE inhibited retinal inflammation and angiogenesis by suppressing the nuclear factor kappa B (NF-κB), protein kinase B (Akt) and extracellular signal-regulated kinase (ERK) pathways. Our results demonstrate that SHE has anti-inflammatory and anti-angiogenic potential against retinal diseases. This is the first such study to report on the efficacy of SHE on retinal inflammatory diseases.
Cerebromicrovascular rarefaction is believed to play a central role in cognitive impairment in patients receiving whole-brain irradiation therapy. To elucidate the mechanism underlying the ...deleterious effects of γ-irradiation on the cerebral microcirculation, rat primary cerebromicrovascular endothelial cells (CMVECs) were irradiated in vitro. We found that in CMVECs, γ-irradiation (2-8 Gy) elicited increased DNA damage, which was repaired less efficiently in CMVECs compared with neurons, microglia, and astrocytes. Increased genomic injury in CMVECs associated with increased apoptotic cell death. In the surviving cells, γ-irradiation promotes premature senescence (indicated by SA-β-galactosidase positivity and upregulation of p16 (INK4a) ), which was associated with impaired angiogenic capacity (decreased proliferation and tube-forming capacity). γ-Irradiated CMVECs acquired a senescence-associated secretory phenotype, characterized by upregulation of proinflammatory cytokines and chemokines (including IL-6, IL-1α, and MCP-1). Collectively, increased vulnerability of γ-irradiated CMVECs and their impaired angiogenic capacity likely contribute to cerebromicrovascular rarefaction and prevent regeneration of the microvasculature postirradiation. The acquisition of a senescence-associated secretory phenotype in irradiated CMVECs is biologically highly significant as changes in the cytokine microenvironment in the hippocampus may affect diverse biological processes relevant for normal neuronal function (including regulation of neurogenesis and the maintenance of the blood brain barrier).
There is increasing evidence that age-associated chronic low-grade inflammation promotes the development of both large-vessel disease (myocardial infarction, stroke, peripheral arterial disease) and ...small-vessel pathologies (including vascular cognitive impairment) in older persons. However, the source of age-related chronic vascular inflammation remains unclear. To test the hypothesis that cell-autonomous mechanisms contribute to the proinflammatory changes in vascular phenotype that accompanies advancing age, we analyzed the cytokine secretion profile of primary vascular smooth muscle cells (VSMCs) derived from young (∼13 years old) and aged (∼21 years old) Macaca mulatta. Aged VSMCs cultured in the absence of systemic factors exhibited significantly increased secretion of interleukin-1β, MCP-1, and tumor necrosis factorα compared with young control cells. Secretion of interleukin-6 also tended to increase in aged VSMCs. This age-associated proinflammatory shift in the cellular secretory phenotype was associated with an increased mitochondrial O(2)(-) production and nuclear factor κ-light-chain-enhancer of activated B cells activation. Treatment of aged VSMCs with a physiologically relevant concentration of resveratrol (1 μM) exerted significant anti-inflammatory effects, reversing aging-induced alterations in the cellular cytokine secretion profile and inhibiting nuclear factor κ-light-chain-enhancer of activated B cells. Resveratrol also attenuated mitochondrial O(2)(-) production and upregulated the transcriptional activity of Nrf2 in aged VSMCs. Thus, in non-human primates, cell-autonomous activation of nuclear factor κ-light-chain-enhancer of activated B cells and expression of an inflammatory secretome likely contribute to vascular inflammation in aging. Resveratrol treatment prevents the proinflammatory properties of the aged VSMC secretome, an effect that likely contributes to the demonstrated vasoprotective action of resveratrol in animal models of aging.
Obesity in the elderly individuals is increasing at alarming rates and there is evidence suggesting that elderly individuals are more vulnerable to the deleterious cardiovascular effects of obesity ...than younger individuals. However, the specific mechanisms through which aging and obesity interact to promote the development of cardiovascular disease remain unclear. The present study was designed to test the hypothesis that aging exacerbates obesity-induced inflammation in perivascular adipose tissue, which contributes to increased vascular oxidative stress and inflammation in a paracrine manner. To test this hypothesis, we assessed changes in the secretome, reactive oxygen species production, and macrophage infiltration in periaortic adipose tissue of young (7 month old) and aged (24 month old) high-fat diet-fed obese C57BL/6 mice. High-fat diet-induced vascular reactive oxygen species generation significantly increased in aged mice, which was associated with exacerbation of endothelial dysfunction and vascular inflammation. In young animals, high-fat diet-induced obesity promoted oxidative stress in the perivascular adipose tissue, which was associated with a marked proinflammatory shift in the profile of secreted cytokines and chemokines. Aging exacerbated obesity-induced oxidative stress and inflammation and significantly increased macrophage infiltration in periaortic adipose tissue. Using cultured arteries isolated from young control mice, we found that inflammatory factors secreted from the perivascular fat tissue of obese aged mice promote significant prooxidative and proinflammatory phenotypic alterations in the vascular wall, mimicking the aging phenotype. Overall, our findings support an important role for localized perivascular adipose tissue inflammation in exacerbation of vascular oxidative stress and inflammation in aging, an effect that likely enhances the risk for development of cardiovascular diseases from obesity in the elderly individuals.
ABSTRACT
With high-resolution spectroscopy, we can study exoplanet atmospheres and learn about their chemical composition, temperature profiles, and presence of clouds and winds, mainly in hot, giant ...planets. State-of-the-art instrumentation is pushing these studies towards smaller exoplanets. Of special interest are the few planets in the ‘Neptune desert’, a lack of Neptune-sized planets in close orbits around their hosts. Here, we assess the presence of water in one such planet, the bloated super-Neptune WASP-166 b, which orbits an F9-type star in a short orbit of 5.4 d. Despite its close-in orbit, WASP-166 b preserved its atmosphere, making it a benchmark target for exoplanet atmosphere studies in the desert. We analyse two transits observed in the visible with ESPRESSO. We clean the spectra from the Earth’s telluric absorption via principal component analysis, which is crucial to the search for water in exoplanets. We use a cross-correlation-to-likelihood mapping to simultaneously estimate limits on the abundance of water and the altitude of a cloud layer, which points towards a low water abundance and/or high clouds. We tentatively detect a water signal blue-shifted ∼5 $\mathrm{km\, s^{-1}}$ from the planetary rest frame. Injection and retrieval of model spectra show that a solar-composition, cloud-free atmosphere would be detected at high significance. This is only possible in the visible due to the capabilities of ESPRESSO and the collecting power of the VLT. This work provides further insight on the Neptune desert planet WASP-166 b, which will be observed with JWST.
ABSTRACT
The hot Neptune desert, a distinct lack of highly irradiated planets in the size range of Neptune, remains one of the most intriguing results of exoplanet population studies. A deeper ...understanding of the atmosphere of exoplanets sitting at the edge or even within the Neptune desert will allow us to better understand if planetary formation or evolution processes are at the origin of the desert. A detection of sodium in WASP-166 b was presented previously with tentative line broadening at the $3.4\, \sigma$ with the HARPS spectrograph. We update this result with two transits observed with the ESPRESSO spectrograph, confirming the detection in each night and the broadened character of the line. This result marks the first confirmed resolved sodium detection within the Neptune desert. In this work, we additionally highlight the importance of treating low-SNR spectral regions particularly where absorption lines of stellar sodium and planetary sodium overlap at mid transit – an important caveat for future observations of the system.
There is a great deal of interest in identifying new chemopreventive agents for colorectal cancer, one of the leading causes of cancer-related death. One promising group of candidates is the ...polyphenols; being natural compounds with high structural diversity, they have a very wide spectrum of anti-inflammatory, anti-oxidant and anti-cancer properties. The present study reports for the first time that spent hops extract (SHE) inhibits the angiogenesis, invasion and migration of SW-480 and HT-29 colorectal adenocarcinoma cells; after incubation with 200 μg/mL SHE, SW-480 and HT-29 cell invasion fell by 98.5% and 89% vs. controls, and migration was inhibited by 99% and 88% vs. controls. These changes were accompanied by a decline of matrix metalloproteinase 2 (MMP-2) and MMP-9 expression and activity. In addition, SHE reduced the expression of vascular endothelial growth factor and hypoxia-inducible factor 1α for both cell lines, indicating that the tested extract has anti-angiogenic potential. In conclusion, our data shows that SHE may be an effective chemopreventive agent acting via the inhibition of angiogenesis, invasion and migration of colorectal cancer cells.
PDF
