Regulation of metabolism by miR-378

The present invention provides a method of regulating fatty acid metabolism in a cell by contacting the cell with a modulator of miR-378 and/or miR-378* activity or expression. The present invention also provides a method of treating or preventing a metabolic disorder, such as obesity, diabetes, or metabolic syndrome, in a subject by administering to the subject an inhibitor of miR-378 and/or miR-378* expression or activity. Methods of treating or preventing pathologic cardiac hypertrophy, cardiac remodeling, myocardial infarction, or heart failure in a subject by inhibiting the expression or activity of miR-378 and/or miR-378* in a subject are also disclosed.Board of Regents, University of Texas Syste

Educomunicação em Tempos de Pandemia:

Os textos que compõem esta obra são oriundos do VIII Colóquio Ibero-americano de Educomunicação (VIII CIEducom) e IX Colóquio Catarinense de Educomunicação (IX CCEducom), realizados em março de 2021. Em um ano no qual o vírus SARS-CoV-2 e variantes circularam por diversos territórios, Educomunicação em tempos de pandemia: práticas e desafios foi o tema discutido nos eventos. Este livro colocado à disposição do público é um modo de compartilhar caminhos e convidar pessoas curiosas a percorrerem, por meio das palavras e recursos gráficos, desafios identificados e estratégias para o enfrentamento deste inesperado período de pandemia

Regulation of Metabolic Processes by Micrornas and Class I Histone Deacetylases

Obesity is a medical condition resulting from accumulation of excess body fat that affects more than 30% of the adult population in the U.S. Obesity-related pathological conditions include heart disease, stroke, type 2 diabetes and certain types of cancer. Despite the high incidence and the elevated social costs, the molecular basis of obesity and associated metabolic syndrome are still poorly understood. Yet, the need for novel therapeutic approaches for the treatment and prevention of obesity remains. In humans and animal model of disease, hallmarks of obesity include dysregulation of genes involved in mitochondrial function, lipid uptake and lipid storage. The dynamic and modifiable regulation of transcriptional pathways that control mitochondrial function and adipogenesis, as well as additional aspects of mammalian metabolism, will provide new approaches for pharmacological intervention in obesity. Thus, the modulation of epigenetic histone modifications and microRNA functions represents a potentially powerful approach for the treatment of metabolic disorders. We show that the Ppargc1b gene, which encodes the PGC-1β protein, also co-transcribes two microRNAs, miR-378 and miR-378*. Mice lacking miR-378/378* are resistant to high fat diet-induced obesity and display enhanced mitochondrial fatty acid metabolism and elevated oxidative capacity of insulin-target tissues. Taken together, our findings reveal that miR-378 and miR-378* function as integral components of the regulatory circuit formed by PGC-1beta and nuclear hormone receptors to control the overall oxidative capacity and energy homeostasis of insulin-target tissues. MiR-378/378* mutant mice do not display overt phenotypes under normal laboratory conditions, whereas their phenotypes become apparent under conditions of stress, in this case in response to excessive caloric intake. Thus, pharmacological modulation of miR-378/378* function might represent an effective approach in the treatment of obesity. In obese humans and mice, the unused caloric energy resulting from excessive net caloric intake is converted to triglycerides and stored in adipocytes for further usage. Lipid accumulation within adipocytes is under the control of a cascade of transcription factors that interact with histone acetyltransferases and deacetylases. We show that histone deacetylase inhibitors efficiently block adipocyte differentiation in vitro. Furthermore, through a loss-of-function approach, we provide evidence that histone deacetylases 1 and 2 play redundant and requisite roles in adipogenesis. In conclusion, we unveiled previously unrecognized roles for miR-378/378* in the control of mitochondrial metabolism and energy homeostasis, and for histone deacetylases in the control of adipocyte differentiation

The imprint of extreme climate events in century-long time series of wood anatomical traits in high-elevation conifers

Extreme climate events are of key importance for forest ecosystems. However, both the inherent infrequency, stochasticity and multiplicity of extreme climate events, and the array of biological responses, challenges investigations. To cope with the long life cycle of trees and the paucity of the extreme events themselves, our inferences should be based on long-term observations. In this context, tree rings and the related xylem anatomical traits represent promising sources of information, due to the wide time perspective and quality of the information they can provide. Here we test, on two high-elevation conifers (Larix decidua and Picea abies sampled at 2100 m a.s.l. in the Eastern Alps), the associations among temperature extremes during the growing season and xylem anatomical traits, specifically the number of cells per ring (CN), cell wall thickness (CWT), and cell diameter (CD). To better track the effect of extreme events over the growing season, tree rings were partitioned in 10 sectors. Climate variability has been reconstructed, for 1800–2011 at monthly resolution and for 1926–2011 at daily resolution, by exploiting the excellent availability of very long and high quality instrumental records available for the surrounding area, and taking into account the relationship between meteorological variables and site topographical settings. Summer temperature influenced anatomical traits of both species, and tree-ring anatomical profiles resulted as being associated to temperature extremes. Most of the extreme values in anatomical traits occurred with warm (positive extremes) or cold (negative) conditions. However, 0–34% of occurrences did not match a temperature extreme event. Specifically, CWT and CN extremes were more clearly associated to climate than CD, which presented a bias to track cold extremes. Dendroanatomical analysis, coupled to high-quality daily-resolved climate records, seems a promising approach to study the effects of extreme events on trees, but further investigations are needed to improve our comprehension of the critical role of such elusive events in forest ecosystems

Vitamin B12 deficiency-induced pseudothrombotic microangiopathy without macrocytosis presenting with acute renal failure: a case report

Abstract Background Vitamin B12 deficiency-induced thrombotic microangiopathy, known as pseudothrombotic microangiopathy, is a rare condition which resembles the clinical features of thrombotic thrombocytopenic purpura but requires a markedly different treatment. Most cases of vitamin B12 deficiency have only mild hematological findings, but in approximately 10% of patients life-threatening conditions have been reported. Case presentation We report a case of a 46-year-old Moroccan man presenting with severe hemolytic anemia, thrombocytopenia, and renal failure in absence of macrocytosis, thus mimicking a genuine thrombotic thrombocytopenic purpura. Rapid improvement of renal function observed with only hydration and transfusions of packed red blood cells and the presence of pancytopenia suggested a bone marrow deficiency associated to a hemolytic component of unclear origin. Detection of low levels of vitamin B12 and rapid restitutio ad integrum with its replacement supported the diagnosis of pseudothrombotic thrombocytopenic purpura caused by vitamin B12 deficiency. Conclusions Diagnosis of pseudothrombotic thrombocytopenic purpura caused by vitamin B12 deficiency might be difficult. Awareness of clinicians toward this differential diagnosis might spare patients from unnecessary therapeutic plasma exchange that is burdened by morbidity and mortality

Blue intensity of Swiss stone pine as a high-frequency temperature proxy in the Alps

Tree rings are widely used for climatic reconstructions and for improving our understanding of ongoing climate change in high-altitude sensitive areas. X-ray maximum latewood density is a very powerful parameter to reconstruct past climatic variations, especially if compared to tree-ring width, but this method is neither inexpensive nor timesaving. However, blue intensity (BI) has resulted in an excellent maximum wood density surrogate that measures the intensity of refected light from latewood in the blue spectra. This methodology is still considered a prototype parameter, and more data are needed for validation of the method. We present the frst BI values coming from Swiss stone pine (Pinus cembra L.) collected on the southern margin of the Alps. Analyses were performed by testing diferent solvents and polishing techniques, as well as diferent CooRecorder pixel percentage settings. The results demonstrate that solvents and software parameters have little infuence on the fnal chronologies. Dendroclimatic analyses demonstrate that Swiss stone pine BI can be a useful tool to extract at least the high-frequency variations in July–August temperatures with a correlation coefcient of up to 0.6 (over the 1800–2017 time period). The immunity of Swiss stone pine to insect defoliator outbreaks further enhances the reliability of the BI values of this species in reconstructing past high-frequency temperature variations in high-altitude sensitive areas

Learning Force Field Parameters from Differentiable Particle-Field Molecular Dynamics

We develop ∂-HylleraasMD (∂-HyMD), a fully end-to-end differentiable molecular dynamics software based on the Hamiltonian hybrid particle-field formalism, and use it to establish a protocol for automated optimization of force field parameters. ∂-HyMD is templated on the recently established HylleraaasMD software, while using the JAX autodiff framework as the main engine for the differentiable dynamics. ∂-HyMD exploits an embarrassingly parallel optimization algorithm by spawning independent simulations, whose trajectories are simultaneously processed by reverse mode automatic differentiation to calculate the gradient of the loss function, which is in turn used for iterative optimization of the force-field parameters. We show that parallel organization facilitates the convergence of the minimization procedure, avoiding the known memory and numerical stability issues of differentiable molecular dynamics approaches. We showcase the effectiveness of our implementation by producing a library of force field parameters for standard phospholipids, with either zwitterionic or anionic heads, and with saturated or unsaturated tails. Compared to the all-atom reference, the force field obtained by ∂-HyMD yields better density profiles than the parameters derived from previously utilized gradient-free optimization procedures. Moreover, ∂-HyMD models can predict with good accuracy properties not included in the learning objective, such as lateral pressure profiles, and are transferable to other systems, including triglycerides

Can Polarity-Inverted Surfactants Self-Assemble in Nonpolar Solvents?

We investigate the self-assembly process of a surfactant with inverted polarity in water and cyclohexane using both all-atom and coarse-grained hybrid particle-field molecular dynamics simulations. Unlike conventional surfactants, the molecule under study, proposed in a recent experiment, is formed by a rigid and compact hydrophobic adamantane moiety, and a long and floppy triethylene glycol tail. In water, we report the formation of stable inverted micelles with the adamantane heads grouping together into a hydrophobic core and the tails forming hydrogen bonds with water. By contrast, microsecond simulations do not provide evidence of stable micelle formation in cyclohexane. Validating the computational results by comparison with experimental diffusion constant and small-angle X-ray scattering intensity, we show that at laboratory thermodynamic conditions the mixture resides in the supercritical region of the phase diagram, where aggregated and free surfactant states coexist in solution. Our simulations also provide indications as to how to escape this region to produce thermodynamically stable micellar aggregates

HylleraasMD: A Domain Decomposition-Based Hybrid Particle-Field Software for Multi-Scale Simulations of Soft Matter

We present HylleraasMD (HyMD), a comprehensive implementation of the recently proposed Hamiltonian formulation of hybrid particle-field molecular dynamics (hPF). The methodology is based on tunable, grid-independent length-scale of coarse graining, obtained by filtering particle densities in reciprocal space. This enables systematic convergence of energies and forces by grid refinement, also eliminating non-physical force aliasing. Separating the time integration of fast modes associated with internal molecular motion, from slow modes associated with their density fields, we implement the first time-reversible hPF simulations. HyMD comprises the optional use of explicit electrostatics, which, in this formalism, corresponds to the long-range potential in Particle-Mesh Ewald. We demonstrate the ability of HhPF to perform simulations in the microcanonical and canonical ensembles with a series of test cases, comprising lipid bilayers and vesicles, surfactant micelles, and polypeptide chains, comparing our results to established literature. An on-the-fly increase of the characteristic coarse graining length significantly speeds up dynamics, accelerating self-diffusion and leading to expedited aggregation. Exploiting this acceleration, we find that the time scales involved in the self-assembly of polymeric structures can lie in the tens to hundreds of picoseconds instead of the multi microsecond regime observed with comparable coarse-grained models