ABSTRACT
We study tidal dissipation in stars with masses in the range 0.1–1.6 M⊙ throughout their evolution, including turbulent effective viscosity acting on equilibrium tides and inertial waves ...(IWs) in convection zones, and internal gravity waves in radiation zones. We consider a range of stellar evolutionary models and incorporate the frequency-dependent effective viscosity acting on equilibrium tides based on the latest simulations. We compare the tidal flow and dissipation obtained with the conventional equilibrium tide, which is strictly invalid in convection zones, finding that the latter typically overpredicts the dissipation by a factor of 2–3. Dissipation of IWs is computed using a frequency-averaged formalism accounting for realistic stellar structure for the first time, and is the dominant mechanism for binary circularization and synchronization on the main sequence. Dissipation of gravity waves in the radiation zone assumes these waves to be fully damped (e.g. by wave breaking), and is the dominant mechanism for planetary orbital decay. We calculate the critical planetary mass required for wave breaking as a function of stellar mass and age, and show that this mechanism predicts destruction of many hot Jupiters but probably not Earth-mass planets on the main sequence. We apply our results to compute tidal quality factors following stellar evolution, and tidal evolutionary time-scales, for the orbital decay of hot Jupiters, and the spin synchronization and circularization of binary stars. We also provide predictions for shifts in transit arrival times due to tidally driven orbital decay of hot Jupiters that may be detected with NGTS, TESS, or PLATO.
This report provides a historical overview of research concerning the endogenous hallucinogen N, N-dimethyltryptamine (DMT), focusing on data regarding its biosynthesis and metabolism in the brain ...and peripheral tissues, methods and results for DMT detection in body fluids and brain, new sites of action for DMT, and new data regarding its possible physiological and therapeutic roles. Research that further elaborates its consideration as a putative neurotransmitter is also addressed. Taking these studies together, the report proposes several new directions and experiments to ascertain the role of DMT in the brain, including brain mapping of enzymes responsible for the biosynthesis of DMT, further studies to elaborate its presence and role in the pineal gland, a reconsideration of binding site data, and new administration and imaging studies. The need to resolve the "natural" role of an endogenous hallucinogen from the effects observed from peripheral administration are also emphasized.
Understanding human embryonic ventral midbrain is of major interest for Parkinson’s disease. However, the cell types, their gene expression dynamics, and their relationship to commonly used rodent ...models remain to be defined. We performed single-cell RNA sequencing to examine ventral midbrain development in human and mouse. We found 25 molecularly defined human cell types, including five subtypes of radial glia-like cells and four progenitors. In the mouse, two mature fetal dopaminergic neuron subtypes diversified into five adult classes during postnatal development. Cell types and gene expression were generally conserved across species, but with clear differences in cell proliferation, developmental timing, and dopaminergic neuron development. Additionally, we developed a method to quantitatively assess the fidelity of dopaminergic neurons derived from human pluripotent stem cells, at a single-cell level. Thus, our study provides insight into the molecular programs controlling human midbrain development and provides a foundation for the development of cell replacement therapies.
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•Species differences in developmental timing and cell proliferation•Multiple radial glia subtypes biased toward distinct fates•Adult dopaminergic neuron subtypes emerge postnatally•A machine learning method to score dopaminergic differentiation of stem cells
Analyzing the time course of ventral midbrain development in mouse, human, and stem cells by single-cell RNA-sequencing provides insight into dopaminergic neuron development and offers a strategy to assess the composition of stem-cell-derived preparations for clinical applications.
ABSTRACT
In close exoplanetary systems, tidal interactions drive orbital and spin evolution of planets and stars over long time-scales. Tidally forced inertial waves (restored by the Coriolis ...acceleration) in the convective envelopes of low-mass stars and giant gaseous planets contribute greatly to the tidal dissipation when they are excited and subsequently damped (e.g. through viscous friction), especially early in the life of a system. These waves are known to be subject to non-linear effects, including triggering differential rotation in the form of zonal flows. In this study, we use a realistic tidal body forcing to excite inertial waves through the residual action of the equilibrium tide in the momentum equation for the waves. By performing 3D non-linear hydrodynamical simulations in adiabatic and incompressible convective shells, we investigate how the addition of non-linear terms affects the tidal flow properties, and the energy and angular momentum redistribution. In particular, we identify and justify the removal of terms responsible for unphysical angular momentum evolution observed in a previous numerical study. Within our new set-up, we observe the establishment of strong cylindrically sheared zonal flows, which modify the tidal dissipation rates from prior linear theoretical predictions. We demonstrate that the effects of this differential rotation on the waves neatly explains the discrepancies between linear and non-linear dissipation rates in many of our simulations. We also highlight the major role of both corotation resonances and parametric instabilities of inertial waves, which are observed for sufficiently high tidal forcing amplitudes or low viscosities, in affecting the tidal flow response.
The ability to repair or promote regeneration within the adult human brain has been envisioned for decades. Until recently, such efforts mainly involved delivery of growth factors and cell ...transplants designed to rescue or replace a specific population of neurons, and the results have largely been disappointing. New approaches using stem-cell-derived cell products and direct cell reprogramming have opened up the possibility of reconstructing neural circuits and achieving better repair. In this Review we briefly summarize the history of neural repair and then discuss these new therapeutic approaches, especially with respect to chronic neurodegenerative disorders.
Parkinson disease (PD) is characterized by loss of the A9 nigral neurons that provide dopaminergic innervation to the striatum. This discovery led to the successful instigation of dopaminergic drug ...treatments in the 1960s, although these drugs were soon recognized to lose some of their efficacy and generate their own adverse effects over time. Despite the fact that PD is now known to have extensive non-nigral pathology with a wide range of clinical features, dopaminergic drug therapies are still the mainstay of therapy, and work well for many years. Given the success of pharmacological dopamine replacement, pursuit of cell-based dopamine replacement strategies seemed to be the next logical step, and studies were initiated over 30 years ago to explore the possibility of dopaminergic cell transplantation. In this Review, we outline the history of this therapeutic approach to PD and highlight the lessons that we have learned en route. We discuss how the best clinical outcomes have been obtained with fetal ventral mesencephalic allografts, while acknowledging inconsistencies in the results owing to problems in trial design, patient selection, tissue preparation, and immunotherapy used post-grafting. We conclude by discussing the challenges of bringing the new generation of stem cell-derived dopamine cells to the clinic.
We explore the linear stability of astrophysical discs exhibiting vertical shear, which arises when there is a radial variation in the temperature or entropy. Such discs are subject to a ...‘vertical-shear instability’, which recent non-linear simulations have shown to drive hydrodynamic activity in the MRI-stable regions of protoplanetary discs. We first revisit locally isothermal discs using the quasi-global reduced model derived by Nelson et al. This analysis is then extended to global axisymmetric perturbations in a cylindrical domain. We also derive and study a reduced model describing discs with power-law radial entropy profiles (‘locally polytropic discs’), which are somewhat more realistic in that they possess physical (as opposed to numerical) surfaces. The fastest growing modes have very short wavelengths and are localized at the disc surfaces (if present), where the vertical shear is maximal. An additional class of modestly growing vertically global body modes is excited, corresponding to destabilized classical inertial waves (‘r modes’). We discuss the properties of both types of modes, and stress that those that grow fastest occur on the shortest available length-scales (determined either by the numerical grid or the physical viscous length). This ill-posedness makes simulations of the instability difficult to interpret. We end with some brief speculation on the non-linear saturation and resulting angular momentum transport.
Neurotrophins have been intensively studied and have multiple roles in the brain. Neurotrophins are first synthetized as proneurotrophins and then cleaved intracellularly and extracellularly. ...Increasing evidences demonstrate that proneurotrophins and mature neurotrophins exerts opposing role in the central nervous system. In the present review, we explore the role of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4) and their respective proform in cellular processes related to learning and memory. We focused on their roles in synaptic activity and plasticity in the brain with an emphasis on long-term potentiation, long-term depression, and basal synaptic transmission in the hippocampus and the temporal lobe area. We also discuss new findings on the role of the Val66Met polymorphism on the BDNF propeptide on synaptic activity.
I‐SPY 2 (investigation of serial studies to predict your therapeutic response with imaging and molecular analysis 2) is a process targeting the rapid, focused clinical development of paired oncologic ...therapies and biomarkers. The framework is an adaptive phase II clinical trial design in the neoadjuvant setting for women with locally advanced breast cancer. I‐SPY 2 is a collaborative effort among academic investigators, the National Cancer Institute, the US Food and Drug Administration, and the pharmaceutical and biotechnology industries under the auspices of the Foundation for the National Institutes of Health Biomarkers Consortium.
Clinical Pharmacology & Therapeutics (2009); 86, 1, 97–100 doi:10.1038/clpt.2009.68
The dentate gyrus (DG) of the mammalian hippocampus is hypothesized to mediate pattern separation--the formation of distinct and orthogonal representations of mnemonic information--and also undergoes ...neurogenesis throughout life. How neurogenesis contributes to hippocampal function is largely unknown. Using adult mice in which hippocampal neurogenesis was ablated, we found specific impairments in spatial discrimination with two behavioral assays: (i) a spatial navigation radial arm maze task and (ii) a spatial, but non-navigable, task in the mouse touch screen. Mice with ablated neurogenesis were impaired when stimuli were presented with little spatial separation, but not when stimuli were more widely separated in space. Thus, newborn neurons may be necessary for normal pattern separation function in the DG of adult mice.
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