887 research outputs found
A further 'degree of freedom' in the rotational evolution of stars
Observational and theoretical investigations provide evidence for non-uniform
spot and magnetic flux distributions on rapidly rotating stars, which have a
significant impact on their angular momentum loss rate through magnetised
winds. Supplementing the formalism of MacGregor & Brenner (1991) with a
latitude-dependent magnetised wind model, we analyse the effect of analytically
prescribed surface distributions of open magnetic flux with different shapes
and degrees of non-uniformity on the rotational evolution of a solar-like star.
The angular momentum redistribution inside the star is treated in a qualitative
way, assuming an angular momentum transfer between the rigidly-rotating
radiative and convective zones on a constant coupling timescale of 15 Myr; for
the sake of simplicity we disregard interactions with circumstellar disks. We
find that non-uniform flux distributions entail rotational histories which
differ significantly from those of classical approaches, with differences
cumulating up to 200% during the main sequence phase. Their impact is able to
mimic deviations of the dynamo efficiency from linearity of up to 40% and
nominal dynamo saturation limits at about 35 times the solar rotation rate.
Concentrations of open magnetic flux at high latitudes thus assist in the
formation of very rapidly rotating stars in young open clusters, and ease the
necessity for a dynamo saturation at small rotation rates. However, since our
results show that even minor amounts of open flux at intermediate latitudes, as
observed with Zeeman-Doppler imaging techniques, are sufficient to moderate
this reduction of the AM loss rate, we suggest that non-uniform flux
distributions are a complementary rather than an alternative explanation for
very rapid stellar rotation.Comment: 12 pages, 13 figures, accepted for publication by A&
The Multifaceted Neurotoxicity of Astrocytes in Ageing and Age-Related Neurodegenerative Diseases: A Translational Perspective.
In a healthy physiological context, astrocytes are multitasking cells contributing to central nervous system (CNS) homeostasis, defense, and immunity. In cell culture or rodent models of age-related neurodegenerative diseases (NDDs), such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), numerous studies have shown that astrocytes can adopt neurotoxic phenotypes that could enhance disease progression. Chronic inflammatory responses, oxidative stress, unbalanced phagocytosis, or alteration of their core physiological roles are the main manifestations of their detrimental states. However, if astrocytes are directly involved in brain deterioration by exerting neurotoxic functions in patients with NDDs is still controversial. The large spectrum of NDDs, with often overlapping pathologies, and the technical challenges associated with the study of human brain samples complexify the analysis of astrocyte involvement in specific neurodegenerative cascades. With this review, we aim to provide a translational overview about the multi-facets of astrocyte neurotoxicity ranging from in vitro findings over mouse and human cell-based studies to rodent NDDs research and finally evidence from patient-related research. We also discuss the role of ageing in astrocytes encompassing changes in physiology and response to pathologic stimuli and how this may prime detrimental responses in NDDs. To conclude, we discuss how potentially therapeutic strategies could be adopted to alleviate or reverse astrocytic toxicity and their potential to impact neurodegeneration and dementia progression in patients
Planet Migration and Disk Destruction due to Magneto-Centrifugal Stellar Winds
This paper investigates the influence of magneto-centrifugally driven or
simply magnetic winds of rapidly-rotating, strongly-magnetized T Tauri stars in
causing the inward or outward migration of close-in giant planets. The
azimuthal ram pressure of the magnetized wind acting on the planet tends to
increase the planet's angular momentum and cause outward migration if the
star's rotation period is less than the planet's orbital period . In
the opposite case, , the planet migrates inward. Thus, planets
orbiting at distances larger (smaller) than
tend to be pushed outward (inward), where is the rotation period of the
star assumed to have the mass of the sun. The magnetic winds are likely to
occur in T Tauri stars where the thermal speed of the gas close to the star is
small, where the star's magnetic field is strong, and where the star rotates
rapidly. The time-scale for appreciable radial motion of the planet is
estimated as Myr. A sufficiently massive close-in planet may
cause tidal locking and once this happens the radial migration due to the
magnetic wind ceases. The magnetic winds are expected to be important for
planet migration for the case of a multipolar magnetic field rather than a
dipole field where the wind is directed away from the equatorial plane and
where a magnetospheric cavity forms. The influence of the magnetic wind in
eroding and eventually destroying the accretion disk is analyzed. A momentum
integral is derived for the turbulent wind/disk boundary layer and this is used
to estimate the disk erosion time-scale as Myr, with the lower
value favored.Comment: 8 pages, 6 figure
Enhanced lithium depletion in Sun-like stars with orbiting planets
The surface abundance of lithium on the Sun is 140 times less than
protosolar, yet the temperature at the base of the surface convective zone is
not hot enough to burn Li. A large range of Li abundances in solar type stars
of the same age, mass and metallicity is observed, but theoretically difficult
to understand. An earlier suggestion that Li is more depleted in stars with
planets was weakened by the lack of a proper comparison sample of stars without
detected planets. Here we report Li abundances for an unbiased sample of
solar-analogue stars with and without detected planets. We find that the
planet-bearing stars have less than 1 per cent of the primordial Li abundance,
while about 50 per cent of the solar analogues without detected planets have on
average 10 times more Li. The presence of planets may increase the amount of
mixing and deepen the convective zone to such an extent that the Li can be
burned.Comment: 13 pages, 2 figure
Normal and Pathological NRF2 Signalling in the Central Nervous System
The nuclear factor erythroid 2-related factor 2 (NRF2) was originally described as a master
regulator of antioxidant cellular response, but in the time since, numerous important biological
functions linked to cell survival, cellular detoxification, metabolism, autophagy, proteostasis, inflammation, immunity, and differentiation have been attributed to this pleiotropic transcription factor that regulates hundreds of genes. After 40 years of in-depth research and key discoveries, NRF2 is now at the center of a vast regulatory network, revealing NRF2 signalling as increasingly complex. It is widely recognized that reactive oxygen species (ROS) play a key role in human physiological and pathological processes such as ageing, obesity, diabetes, cancer, and neurodegenerative diseases. The high oxygen consumption associated with high levels of free iron and oxidizable unsaturated lipids make the brain particularly vulnerable to oxidative stress. A good stability of NRF2 activity is thus crucial to maintain the redox balance and therefore brain homeostasis. In this review, we have gathered recent data about the contribution of the NRF2 pathway in the healthy brain as well as during metabolic diseases, cancer, ageing, and ageing-related neurodegenerative diseases. We also discuss promising therapeutic strategies and the need for better understanding of cell-type-specific functions of NRF2 in these different fields
The experimental power of FR900359 to study Gq-regulated biological processes
Despite the discovery of heterotrimeric αβγ G proteins ∼25 years ago, their selective perturbation by cell-permeable inhibitors remains a fundamental challenge. Here we report that the plant-derived depsipeptide FR900359 (FR) is ideally suited to this task. Using a multifaceted approach we systematically characterize FR as a selective inhibitor of Gq/11/14 over all other mammalian Gα isoforms and elaborate its molecular mechanism of action. We also use FR to investigate whether inhibition of Gq proteins is an effective post-receptor strategy to target oncogenic signalling, using melanoma as a model system. FR suppresses many of the hallmark features that are central to the malignancy of melanoma cells, thereby providing new opportunities for therapeutic intervention. Just as pertussis toxin is used extensively to probe and inhibit the signalling of Gi/o proteins, we anticipate that FR will at least be its equivalent for investigating the biological relevance of Gq. Pertussis toxin is used extensively for perturbing Gαi/o pathways in the study of physiology and disease, but an equivalent inhibitor of Gαq signalling is not currently available to the research community. Here the authors characterize FR900359 as a specific Gq inhibitor and demonstrate its utility to dissect GPCR signalling and its potential to inhibit melanoma cells
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Human MC4R variants affect endocytosis, trafficking and dimerization revealing multiple cellular mechanisms involved in weight regulation.
The Melanocortin-4 Receptor (MC4R) plays a pivotal role in energy homeostasis. We used human MC4R mutations associated with an increased or decreased risk of obesity to dissect mechanisms that regulate MC4R function. Most obesity-associated mutations impair trafficking to the plasma membrane (PM), whereas obesity-protecting mutations either accelerate recycling to the PM or decrease internalization, resulting in enhanced signaling. MC4R mutations that do not affect canonical Gαs protein-mediated signaling, previously considered to be non-pathogenic, nonetheless disrupt agonist-induced internalization, β-arrestin recruitment, and/or coupling to Gαs, establishing their causal role in severe obesity. Structural mapping reveals ligand-accessible sites by which MC4R couples to effectors and residues involved in the homodimerization of MC4R, which is disrupted by multiple obesity-associated mutations. Human genetic studies reveal that endocytosis, intracellular trafficking, and homodimerization regulate MC4R function to a level that is physiologically relevant, supporting the development of chaperones, agonists, and allosteric modulators of MC4R for weight loss therapy
Human MC4R variants affect endocytosis, trafficking and dimerization revealing multiple cellular mechanisms involved in weight regulation.
The Melanocortin-4 Receptor (MC4R) plays a pivotal role in energy homeostasis. We used human MC4R mutations associated with an increased or decreased risk of obesity to dissect mechanisms that regulate MC4R function. Most obesity-associated mutations impair trafficking to the plasma membrane (PM), whereas obesity-protecting mutations either accelerate recycling to the PM or decrease internalization, resulting in enhanced signaling. MC4R mutations that do not affect canonical Gαs protein-mediated signaling, previously considered to be non-pathogenic, nonetheless disrupt agonist-induced internalization, β-arrestin recruitment, and/or coupling to Gαs, establishing their causal role in severe obesity. Structural mapping reveals ligand-accessible sites by which MC4R couples to effectors and residues involved in the homodimerization of MC4R, which is disrupted by multiple obesity-associated mutations. Human genetic studies reveal that endocytosis, intracellular trafficking, and homodimerization regulate MC4R function to a level that is physiologically relevant, supporting the development of chaperones, agonists, and allosteric modulators of MC4R for weight loss therapy
Mapping physiological G protein-coupled receptor signaling pathways reveals a role for receptor phosphorylation in airway contraction.
G protein-coupled receptors (GPCRs) are known to initiate a plethora of signaling pathways in vitro. However, it is unclear which of these pathways are engaged to mediate physiological responses. Here, we examine the distinct roles of Gq/11-dependent signaling and receptor phosphorylation-dependent signaling in bronchial airway contraction and lung function regulated through the M3-muscarinic acetylcholine receptor (M3-mAChR). By using a genetically engineered mouse expressing a G protein-biased M3-mAChR mutant, we reveal the first evidence, to our knowledge, of a role for M3-mAChR phosphorylation in bronchial smooth muscle contraction in health and in a disease state with relevance to human asthma. Furthermore, this mouse model can be used to distinguish the physiological responses that are regulated by M3-mAChR phosphorylation (which include control of lung function) from those responses that are downstream of G protein signaling. In this way, we present an approach by which to predict the physiological/therapeutic outcome of M3-mAChR-biased ligands with important implications for drug discovery.This study is funded by the Medical Research Council (MRC) through funding of program leaders provided by the MRC Toxicology Unit (to A.B.T.)
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