Of sound mind and body: depression, disease, and accelerated aging

Major depressive disorder (MDD) is associated with a high rate of developing serious medical comorbidities such as cardiovascular disease, stroke, dementia, osteoporosis, diabetes, and the metabolic syndrome. These are conditions that typically occur late in life, and it has been suggested that MDD may be associated with “accelerated aging.” We review several moderators and mediators that may accompany MDD and that may give rise to these comorbid medical conditions. We first review the moderating effects of psychological styles of coping, genetic predisposition, and epigenetic modifications (eg, secondary to childhood adversity). We then focus on several interlinked mediators occurring in MDD (or at least in subtypes of MDD) that may contribute to the medical comorbidity burden and to accelerated aging: limbic-hypothalamic-pituitary-adrenal axis alterations, diminution in glucocorticoid receptor function, altered glucose tolerance and insulin sensitivity, excitotoxicity, increases in intracellular calcium, oxidative stress, a proinflammatory milieu, lowered levels of “counter-regulatory” neurosteroids (such as allopregnanolone and dehydroepiandrosterone), diminished neurotrophic activity, and accelerated cell aging, manifest as alterations in telomerase activity and as shortening of telomeres, which can lead to apoptosis and cell death. In this model, MDD is characterized by a surfeit of potentially destructive mediators and an insufficiency of protective or restorative ones. These factors interact in increasing the likelihood of physical disease and of accelerated aging at the cellular level. We conclude with suggestions for novel mechanism-based therapeutics based on these mediators

bRing: An observatory dedicated to monitoring the β\beta Pictoris b Hill sphere transit

Aims. We describe the design and first light observations from the $\beta$ Pictoris b Ring ("bRing") project. The primary goal is to detect photometric variability from the young star $\beta$ Pictoris due to circumplanetary material surrounding the directly imaged young extrasolar gas giant planet \bpb. Methods. Over a nine month period centred on September 2017, the Hill sphere of the planet will cross in front of the star, providing a unique opportunity to directly probe the circumplanetary environment of a directly imaged planet through photometric and spectroscopic variations. We have built and installed the first of two bRing monitoring stations (one in South Africa and the other in Australia) that will measure the flux of $\beta$ Pictoris, with a photometric precision of $0.5\%$ over 5 minutes. Each station uses two wide field cameras to cover the declination of the star at all elevations. Detection of photometric fluctuations will trigger spectroscopic observations with large aperture telescopes in order to determine the gas and dust composition in a system at the end of the planet-forming era. Results. The first three months of operation demonstrate that bRing can obtain better than 0.5\% photometry on $\beta$ Pictoris in five minutes and is sensitive to nightly trends enabling the detection of any transiting material within the Hill sphere of the exoplanet

Data calibration for the MASCARA and bRing instruments

Aims: MASCARA and bRing are photometric surveys designed to detect variability caused by exoplanets in stars with $m_V < 8.4$. Such variability signals are typically small and require an accurate calibration algorithm, tailored to the survey, in order to be detected. This paper presents the methods developed to calibrate the raw photometry of the MASCARA and bRing stations and characterizes the performance of the methods and instruments. Methods: For the primary calibration a modified version of the coarse decorrelation algorithm is used, which corrects for the extinction due to the earth's atmosphere, the camera transmission, and intrapixel variations. Residual trends are removed from the light curves of individual stars using empirical secondary calibration methods. In order to optimize these methods, as well as characterize the performance of the instruments, transit signals were injected in the data. Results: After optimal calibration an RMS scatter of 10 mmag at $m_V \sim 7.5$ is achieved in the light curves. By injecting transit signals with periods between one and five days in the MASCARA data obtained by the La Palma station over the course of one year, we demonstrate that MASCARA La Palma is able to recover 84.0, 60.5 and 20.7% of signals with depths of 2, 1 and 0.5% respectively, with a strong dependency on the observed declination, recovering 65.4% of all transit signals at $\delta > 0^\circ$ versus 35.8% at $\delta < 0^\circ$. Using the full three years of data obtained by MASCARA La Palma to date, similar recovery rates are extended to periods up to ten days. We derive a preliminary occurrence rate for hot Jupiters around A-stars of ${>} 0.4 \%$, knowing that many hot Jupiters are still overlooked. In the era of TESS, MASCARA and bRing will provide an interesting synergy for finding long-period (${>} 13.5$ days) transiting gas-giant planets around the brightest stars.Comment: 18 pages, 17 figures, accepted for publication in A&

MutLα heterodimers modify the molecular phenotype of Friedreich ataxia

This article has been made available through the Brunel Open Access Publishing Fund.Background: Friedreich ataxia (FRDA), the most common autosomal recessive ataxia disorder, is caused by a dynamic GAA repeat expansion mutation within intron 1 of FXN gene, resulting in down-regulation of frataxin expression. Studies of cell and mouse models have revealed a role for the mismatch repair (MMR) MutS-heterodimer complexes and the PMS2 component of the MutLα complex in the dynamics of intergenerational and somatic GAA repeat expansions: MSH2, MSH3 and MSH6 promote GAA repeat expansions, while PMS2 inhibits GAA repeat expansions. Methodology/Principal Findings: To determine the potential role of the other component of the MutLα complex, MLH1, in GAA repeat instability in FRDA, we have analyzed intergenerational and somatic GAA repeat expansions from FXN transgenic mice that have been crossed with Mlh1 deficient mice. We find that loss of Mlh1 activity reduces both intergenerational and somatic GAA repeat expansions. However, we also find that loss of either Mlh1 or Pms2 reduces FXN transcription, suggesting different mechanisms of action for Mlh1 and Pms2 on GAA repeat expansion dynamics and regulation of FXN transcription. Conclusions/Significance: Both MutLα components, PMS2 and MLH1, have now been shown to modify the molecular phenotype of FRDA. We propose that upregulation of MLH1 or PMS2 could be potential FRDA therapeutic approaches to increase FXN transcription. © 2014 Ezzatizadeh et al.This article has been made available through the Brunel Open Access Publishing Fund

Oxidized phospholipids are proinflammatory and proatherogenic in hypercholesterolaemic mice.

Oxidized phospholipids (OxPL) are ubiquitous, are formed in many inflammatory tissues, including atherosclerotic lesions, and frequently mediate proinflammatory changes 1 . Because OxPL are mostly the products of non-enzymatic lipid peroxidation, mechanisms to specifically neutralize them are unavailable and their roles in vivo are largely unknown. We previously cloned the IgM natural antibody E06, which binds to the phosphocholine headgroup of OxPL, and blocks the uptake of oxidized low-density lipoprotein (OxLDL) by macrophages and inhibits the proinflammatory properties of OxPL2-4. Here, to determine the role of OxPL in vivo in the context of atherogenesis, we generated transgenic mice in the Ldlr-/- background that expressed a single-chain variable fragment of E06 (E06-scFv) using the Apoe promoter. E06-scFv was secreted into the plasma from the liver and macrophages, and achieved sufficient plasma levels to inhibit in vivo macrophage uptake of OxLDL and to prevent OxPL-induced inflammatory signalling. Compared to Ldlr-/- mice, Ldlr -/- E06-scFv mice had 57-28% less atherosclerosis after 4, 7 and even 12 months of 1% high-cholesterol diet. Echocardiographic and histologic evaluation of the aortic valves demonstrated that E06-scFv ameliorated the development of aortic valve gradients and decreased aortic valve calcification. Both cholesterol accumulation and in vivo uptake of OxLDL were decreased in peritoneal macrophages, and both peritoneal and aortic macrophages had a decreased inflammatory phenotype. Serum amyloid A was decreased by 32%, indicating decreased systemic inflammation, and hepatic steatosis and inflammation were also decreased. Finally, the E06-scFv prolonged life as measured over 15 months. Because the E06-scFv lacks the functional effects of an intact antibody other than the ability to bind OxPL and inhibit OxLDL uptake in macrophages, these data support a major proatherogenic role of OxLDL and demonstrate that OxPL are proinflammatory and proatherogenic, which E06 counteracts in vivo. These studies suggest that therapies inactivating OxPL may be beneficial for reducing generalized inflammation, including the progression of atherosclerosis, aortic stenosis and hepatic steatosis

Localized precipitation and runoff on Mars

We use the Mars Regional Atmospheric Modeling System (MRAMS) to simulate lake storms on Mars, finding that intense localized precipitation will occur for lake size >=10^3 km^2. Mars has a low-density atmosphere, so deep convection can be triggered by small amounts of latent heat release. In our reference simulation, the buoyant plume lifts vapor above condensation level, forming a 20km-high optically-thick cloud. Ice grains grow to 200 microns radius and fall near (or in) the lake at mean rates up to 1.5 mm/hr water equivalent (maximum rates up to 6 mm/hr water equivalent). Because atmospheric temperatures outside the surface layer are always well below 273K, supersaturation and condensation begin at low altitudes above lakes on Mars. In contrast to Earth lake-effect storms, lake storms on Mars involve continuous precipitation, and their vertical velocities and plume heights exceed those of tropical thunderstorms on Earth. Convection does not reach above the planetary boundary layer for lakes O(10^2) mbar. Instead, vapor is advected downwind with little cloud formation. Precipitation occurs as snow, and the daytime radiative forcing at the land surface due to plume vapor and storm clouds is too small to melt snow directly (<+10 W/m^2). However, if orbital conditions are favorable, then the snow may be seasonally unstable to melting and produce runoff to form channels. We calculate the probability of melting by running thermal models over all possible orbital conditions and weighting their outcomes by probabilities given by Laskar et al., 2004. We determine that for an equatorial vapor source, sunlight 15% fainter than at present, and snowpack with albedo 0.28 (0.35), melting may occur with 4%(0.1%) probability. This rises to 56%(12%) if the ancient greenhouse effect was modestly (6K) greater than today.Comment: Submitted to JGR Planet