miRNA degradation in the mammalian brain Kim, Chun K; Pak, Toni R
American Journal of Physiology: Cell Physiology,
10/2020, Letnik:
319, Številka:
4
Journal Article
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MicroRNAs (miRNAs) are short, noncoding RNAs that are evolutionarily conserved across many different species. miRNA regulation of gene expression, specifically in the context of the mammalian brain, ...has been well characterized; however, the regulation of miRNA degradation is still a focus of ongoing research. This review focuses on recent findings concerning the cellular mechanisms that govern miRNA degradation, with an emphasis on target-mediated miRNA degradation and how this phenomenon is uniquely poised to maintain homeostasis in neuronal systems.
The AMPLIFY trial compared apixaban with enoxaparin followed by warfarin for the treatment of acute venous thromboembolism (VTE).
To perform a subgroup analysis to compare the efficacy and safety of ...apixaban and enoxaparin followed by warfarin for the treatment of VTE in patients with cancer enrolled in AMPLIFY.
Patients with symptomatic VTE were randomized to a 6-month course of apixaban or enoxaparin followed by warfarin. The primary efficacy outcome and principal safety outcome were recurrent VTE or VTE-related death and major bleeding, respectively.
Of the 5395 patients randomized, 169 (3.1%) had active cancer at baseline, and 365 (6.8%) had a history of cancer without active cancer at baseline. Among patients with active cancer, recurrent VTE occurred in 3.7% and 6.4% of evaluable patients in the apixaban and enoxaparin/warfarin groups, respectively (relative risk RR 0.56, 95% confidence interval CI 0.13-2.37); major bleeding occurred in 2.3% and 5.0% of evaluable patients, respectively (RR 0.45, 95% CI 0.08-2.46). Among patients with a history of cancer, recurrent VTE occurred in 1.1% and 6.3% of evaluable patients in the apixaban and enoxaparin/warfarin groups, respectively (RR 0.17, 95% CI 0.04-0.78); major bleeding occurred in 0.5% and 2.8% of treated patients, respectively (RR 0.20, 95% CI 0.02-1.65).
The results of this subgroup analysis suggest that apixaban is a convenient option for cancer patients with VTE. However, additional studies are needed to confirm this concept and to compare apixaban with low molecular weight heparin in these patients.
With the aid of a method of displacement potentials, an efficient and accurate analytical derivation of the three-dimensional dynamic Green’s functions for a transversely isotropic multilayered ...half-space is presented. Constituted by proper algebraic factorizations, a set of generalized transmission–reflection matrices and internal source fields that are free of any numerically unstable exponential terms are proposed for effective computations of the potential solution. Three-dimensional point-load Green’s functions for stresses and displacements are given, for the first time, in the complex-plane line-integral representations. The present formulations and solutions are analytically in exact agreement with the existing solutions given by
Pak and Guzina (2002) for the isotropic case. For the numerical computation of the integrals, a robust and effective methodology which gives the necessary account of the presence of singularities including branch points and poles on the path of integration is laid out. A comparison with the existing numerical solutions for multilayered isotropic half-space is made to confirm the accuracy of the numerical solutions.
Aging and the coincident loss of circulating estrogens at menopause lead to increased risks for neurological and cardiovascular pathologies. Clinical studies show that estrogen therapy (ET) can be ...beneficial in mitigating these negative effects, in both the brain and heart, when it is initiated shortly after the perimenopausal transition. However, this same therapy is detrimental when initiated >10 years postmenopause. Importantly, the molecular mechanisms underlying this age-related switch in ET efficacy are unknown. Estrogen receptors (ERs) mediate the neuroprotective and cardioprotective functions of estrogens by modulating gene transcription or, non-genomically, by activating second messenger signaling pathways, such as mitogen activated protein kinases (MAPK). These kinases are critical regulators of cell signaling pathways and have widespread downstream effects. Our hypothesis is that age and estrogen deprivation following menopause alters the expression and activation of the MAPK family members p38 and ERK in the brain and heart. To test this hypothesis, we used a surgically induced model of menopause in 18 month old rats through bilateral ovariectomy (OVX) followed by an acute dose of 17β-estradiol (E2) administered at varying time points post-OVX (1 week, 4 weeks, 8 weeks, or 12 weeks). Age and E2 treatment differentially regulated kinase activity in both the brain and heart, and the effects were also brain region specific. MAPK signaling plays an integral role in aging, and the aberrant regulation of those signaling pathways might be involved in age-related disorders. Clinical studies show benefits of ET during early menopause but detrimental effects later, which might be reflective of changes in kinase expression and activation status.
Summary
This paper presents a rigorous analysis for the static interaction of a cylindrical thin‐walled pile with an inhomogeneous isotropic elastic half‐space under vertical, horizontal, and ...torsional forces individually applied at the top of pile. The inhomogeneity is specified with the exponential variation of shear modulus along depth of the embedding medium, and the Poisson's ratio is assumed to be constant. By means of a set of Green's functions for pile and soil medium and satisfying the compatibility conditions between the 2 interacting media, the formulation is reduced to coupled Fredholm integral equations. Using the adaptive‐gradient elements, capable of capturing the singular stress transfer at both ends of the pile, a numerical procedure is developed and utilized for evaluating the relevant integral equations and studying the inhomogeneity effect on the soil‐pile interaction responses. The analysis results have been validated for different soil‐pile modulus ratios under axial load and for a Poisson's ratio of 0.3 under lateral load. The procedure does not consider the nonlinear behavior of the soil medium or plastic yielding in the pile section, and the impact of the unreliable results for the case of high Poisson's ratio is not examined.
With the aid of a complete representation using two displacement potentials, an efficient and accurate analytical derivation of the fundamental Green’s functions for a transversely isotropic elastic ...half-space subjected to an arbitrary, time-harmonic, finite, buried source is presented. The formulation includes a complete set of transformed stress-potential and displacement-potential relations that can be useful in a variety of elastodynamic as well as elastostatic problems. The present solutions are analytically in exact agreement with the existing solutions for a half-space with isotropic material properties. For the numerical evaluation of the inversion integrals, a quadrature scheme which gives the necessary account of the presence of singularities including branch points and pole on the path of integration is implemented. The reliability of the proposed numerical scheme is confirmed by comparisons with existing solutions.
Through a rigorous mathematical formulation, this paper considers the axisymmetric interaction analysis of a thin-walled cylindrical pile with finite length embedded in an exponentially graded ...transversely isotropic half-space under axial loads at the top of pile. The action of pile to the embedding medium is represented with axial and radial ring loads and the relevant set of Green's functions for the pile and semi-infinite soil medium has been developed. By satisfying the compatibility conditions between the two interacting media, the interaction analysis is shown to be reducible to a pair of Fredholm integral equations. Due to the complex nature of mathematical formulations and the intrinsic singularity of stress transfer, the analytical solution of obtained boundary integral equations is not possible and a suitable numerical scheme has been developed. By means of adaptive gradient shape functions which are capable of smoothly capturing regular and singular solutions, the given Fredholm integral equations are discretized in the common boundary of interacting media and solved numerically for the interfacial stress components. The numerical procedure is verified through comparisons with previous studies and the effect of inhomogeneity of soil layer on different responses of the interaction process is discussed by presenting several numerical results.
Adolescent binge alcohol abuse induces long-term changes in gene expression, which impacts the physiological stress response and memory formation, two functions mediated in part by the ventral (VH) ...and dorsal (DH) hippocampus. microRNAs (miRs) are small RNAs that play an important role in gene regulation and are potential mediators of long-term changes in gene expression. Two genes important for regulating hippocampal functions include brain-derived neurotrophic factor (BDNF) and sirtuin-1 (SIRT1), which we identified as putative gene targets of miR-10a-5p, miR-26a, miR-103, miR-495. The purpose of this study was to quantify miR-10a-5p, miR-26a, miR-103, miR-495 expression levels in the dorsal and ventral hippocampus of male Wistar rats during normal pubertal development and then assess the effects of repeated binge-EtOH exposure. In addition, we measured the effects of binge EtOH-exposure on hippocampal Drosha and Dicer mRNA levels, as well as the putative miR target genes, BDNF and SIRT1. Overall, mid/peri-pubertal binge EtOH exposure altered the normal expression patterns of all miRs tested in an age- and brain region-dependent manner and this effect persisted for up to 30 days post-EtOH exposure. Moreover, our data revealed that mid/peri-pubertal binge EtOH exposure significantly affected miR biosynthetic processing enzymes, Drosha and Dicer. Finally, EtOH-induced significant changes in the expression of a subset of miRs, which correlated with changes in the expression of their predicted target genes. Taken together, these data demonstrate that EtOH exposure during pubertal development has long-term effects on miRNA expression in the rat hippocampus.
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