Dust in and around galaxies: dust in cluster environments and its impact on gas cooling

Simulating the dust content of galaxies and their surrounding gas is challenging due to the wide range of physical processes affecting the dust evolution. Here we present cosmological hydrodynamical simulations of a cluster of galaxies, $M_\text{200,crit}=6 \times 10^{14}\,{\rm M_\odot}$, including a novel dust model for the moving mesh code {\sc Arepo}. This model includes dust production, growth, supernova-shock-driven destruction, ion-collision-driven thermal sputtering, and high temperature dust cooling through far infrared re-radiation of collisionally deposited electron energies. Adopting a rather low thermal sputtering rate, we find, consistent with observations, a present-day overall dust-to-gas ratio of $\sim 2\times 10^{-5}$, a total dust mass of $\sim 2\times 10^9\,{\rm M_\odot}$, and a dust mass fraction of $\sim 3\times 10^{-6}$. The typical thermal sputtering timescales within $\sim 100\,{\rm kpc}$ are around $\sim 10\,{\rm Myr}$, and increase towards the outer parts of the cluster to $\sim 10^3\,{\rm Myr}$ at a cluster-centric distance of $1\,{\rm Mpc}$. The condensation of gas phase metals into dust grains reduces high temperature metal-line cooling, but also leads to additional dust infrared cooling. The additional infrared cooling changes the overall cooling rate in the outer parts of the cluster, beyond $\sim 1\,{\rm Mpc}$, by factors of a few. This results in noticeable changes of the entropy, temperature, and density profiles of cluster gas once dust formation is included. The emitted dust infrared emission due to dust cooling is consistent with observational constraints.Comment: 14 pages, 10 figures. MNRAS accepte

Advances in Computational Techniques to Study GPCR-Ligand Recognition

G-protein-coupled receptors (GPCRs) are among the most intensely investigated drug targets. The recent revolutions in protein engineering and molecular modeling algorithms have overturned the research paradigm in the GPCR field. While the numerous ligand-bound X-ray structures determined have provided invaluable insights into GPCR structure and function, the development of algorithms exploiting graphics processing units (GPUs) has made the simulation of GPCRs in explicit lipid-water environments feasible within reasonable computation times. In this review we present a survey of the recent advances in structure-based drug design approaches with a particular emphasis on the elucidation of the ligand recognition process in class A GPCRs by means of membrane molecular dynamics (MD) simulations

The current status of pharmacotherapy for the treatment of Parkinson's disease: transition from single-target to multitarget therapy

Parkinson's disease (PD) is a neurodegenerative disorder characterized by degeneration of dopaminergic neurons. Motor features such as tremor, rigidity, bradykinesia and postural instability are common traits of PD. Current treatment options provide symptomatic relief to the condition but are unable to reverse disease progression. The conventional single-target therapeutic approach might not always induce the desired effect owing to the multifactorial nature of PD. Hence, multitarget strategies have been proposed to simultaneously target multiple proteins involved in the development of PD. Herein, we provide an overview of the pathogenesis of PD and the current pharmacotherapies. Furthermore, rationales and examples of multitarget approaches that have been tested in preclinical trials for the treatment of PD are also discussed

Targeting Protein Kinase CK1\u3b4 with Riluzole: Could It Be One of the Possible Missing Bricks to Interpret Its Effect in the Treatment of ALS from a Molecular Point of View?

Riluzole, approved by the US Food and Drug Administration (FDA) in 1995, is the most widespread oral treatment for the fatal neurodegenerative disorder amyotrophic lateral sclerosis (ALS). The drug, whose mechanism of action is still obscure, mitigates progression of the illness, but unfortunately with only limited improvements. Herein we report the first demonstration, using a combination of computational and in vitro studies, that riluzole is an ATP-competitive inhibitor of the protein kinase CK1 isoform\u2005\u3b4, with an IC50 value of 16.1\u2005\u3bcm. This allows us to rewrite its possible molecular mechanism of action in the treatment of ALS. The inhibition of CK1\u3b4 catalytic activity indeed links the two main pathological hallmarks of ALS: transactive response DNA-binding protein of 43\u2005kDa (TDP-43) proteinopathy and glutamate excitotoxicity, exacerbated by the loss of expression of glial excitatory amino acid transporter-2 (EAAT2)

The Multifaceted Role of GPCRs in Amyotrophic Lateral Sclerosis: A New Therapeutic Perspective?

Amyotrophic lateral sclerosis (ALS) is a degenerating disease involving the motor neurons, which causes a progressive loss of movement ability, usually leading to death within 2 to 5 years from the diagnosis. Much effort has been put into research for an effective therapy for its eradication, but still, no cure is available. The only two drugs approved for this pathology, Riluzole and Edaravone, are onlyable to slow down the inevitable disease progression. As assessed in the literature, drug targets such as protein kinases have already been extensively examined as potential drug targets for ALS, with some molecules already in clinical trials. Here, we focus on the involvement of another very important and studied class of biological entities, G protein-coupled receptors (GPCRs), in the onset and progression of ALS. This workaimsto give an overview of what has been already discovered on the topic, providing useful information and insights that can be used by scientists all around the world who are putting efforts into the fight against this very important neurodegenerating disease

¿Qué actualizaciones existen a diciembre de 2021 acerca de la eficacia de dapagliflozina en el tratamiento de pacientes no diabéticos con IC con FEVI reducida?

Maite Inthamoussu: Facultad de Medicina, Universidad de la República. Montevideo, Uruguay -- Federico Garafoni: Facultad de Medicina, Universidad de la República. Montevideo, Uruguay -- Stephanie Viroga: Facultad de Medicina, Universidad de la República. Montevideo, Uruguay -- Noelia Speranza: Facultad de Medicina, Universidad de la República. Montevideo, Urugua

Exploring the flavour structure of the MSSM with rare K decays

We present an extensive analysis of rare K decays, in particular of the two neutrino modes K+->pi+ nu nu-bar and KL->pi0 nu nu-bar, in the Minimal Supersymmetric extension of the Standard Model. We analyse the expectations for the branching ratios of these modes, both within the restrictive framework of the minimal flavour violation hypothesis and within a more general framework with new sources of flavour-symmetry breaking. In both scenarios, the information that can be extracted from precise measurements of the two neutrino modes turn out to be very useful in restricting the parameter space of the model, even after taking into account the possible information on the mass spectrum derived from high-energy colliders, and the constraints from B-physics experiments. In the presence of new sources of flavour-symmetry breaking, additional significant constraints on the model can be derived also from the two KL->pi0 l+l- modes.Comment: 22 pages, 10 figures (high quality figures available on request

Impact of protein-ligand solvation and desolvation on transition state thermodynamic properties of adenosine A2Aligand binding kinetics

Ligand-protein binding kinetic rates are growing in importance as parameters to consider in drug discovery and lead optimization. In this study we analysed using surface plasmon resonance (SPR) the transition state (TS) properties of a set of six adenosine A2Areceptor inhibitors, belonging to both the xanthine and the triazolo-triazine scaffolds. SPR highlighted interesting differences among the ligands in the enthalpic and entropic components of the TS energy barriers for the binding and unbinding events. To better understand at a molecular level these differences, we developed suMetaD, a novel molecular dynamics (MD)-based approach combining supervised MD and metadynamics. This method allows simulation of the ligand unbinding and binding events. It also provides the system conformation corresponding to the highest energy barrier the ligand is required to overcome to reach the final state. For the six ligands evaluated in this study their TS thermodynamic properties were linked in particular to the role of water molecules in solvating/desolvating the pocket and the small molecules. suMetaD identified kinetic bottleneck conformations near the bound state position or in the vestibule area. In the first case the barrier is mainly enthalpic, requiring the breaking of strong interactions with the protein. In the vestibule TS location the kinetic bottleneck is instead mainly of entropic nature, linked to the solvent behaviour