Inhibition of MAPK-Erk pathway in vivo attenuates aortic valve disease processes in Emilin1-deficient mouse model

Aortic valve disease (AVD) is a common condition with a progressive natural history, and presently, there are no pharmacologic treatment strategies. Elastic fiber fragmentation (EFF) is a hallmark of AVD, and increasing evidence implicates developmental elastic fiber assembly defects. Emilin1 is a glycoprotein necessary for elastic fiber assembly that is present in both developing and mature human and mouse aortic valves. The Emilin1‐deficient mouse (Emilin1 (−/−)) is a model of latent AVD, characterized by activated TGFβ/MEK/p‐Erk signaling and upregulated elastase activity. Emilin1 (−/−) aortic valves demonstrate early EFF and aberrant angiogenesis followed by late neovascularization and fibrosis. The objective of this study was to test the effectiveness of three different targeted therapies. Aged (12–14 months) Emilin1 (−/−) mice were treated with refametinib (RDEA‐119, MEK1/2 inhibitor), doxycycline (elastase inhibitor), or G6‐31 (anti‐VEGF‐A mouse antibody) for 4 weeks. Refametinib‐ and doxycycline‐treated Emilin1 (−/−) mice markedly reduced MEK/p‐Erk activation in valve tissue. Furthermore, both refametinib and doxycycline attenuated elastolytic cathepsin K, L, MMP‐2, and MMP‐9 activation, and abrogated macrophage and neutrophil infiltration in Emilin1 (−/−) aortic valves. RNAseq analysis was performed in aortic valve tissue from adult (4 months) and aged (14 months) Emilin1 (−/−) and age‐matched wild‐type control mice, and demonstrated upregulation of genes associated with MAPK/MEK/p‐Erk signaling and elastases at the adult stage and inflammatory pathways at the aged stage controlling for age. These results suggest that Erk1/2 signaling is an important modulator of early elastase activation, and pharmacological inhibition using refametinib may be a promising treatment to halt AVD progressio

Fast convex optimization via inertial dynamics with Hessian driven damping

We first study the fast minimization properties of the trajectories of the second-order evolution equation $$\ddot{x}(t) + \frac{\alpha}{t} \dot{x}(t) + \beta \nabla^2 \Phi (x(t))\dot{x} (t) + \nabla \Phi (x(t)) = 0,$$ where $\Phi:\mathcal H\to\mathbb R$ is a smooth convex function acting on a real Hilbert space $\mathcal H$, and $\alpha$, $\beta$ are positive parameters. This inertial system combines an isotropic viscous damping which vanishes asymptotically, and a geometrical Hessian driven damping, which makes it naturally related to Newton's and Levenberg-Marquardt methods. For $\alpha\geq 3$, $\beta >0$, along any trajectory, fast convergence of the values $$\Phi(x(t))- \min_{\mathcal H}\Phi =\mathcal O\left(t^{-2}\right)$$ is obtained, together with rapid convergence of the gradients $\nabla\Phi(x(t))$ to zero. For $\alpha>3$, just assuming that $\Phi$ has minimizers, we show that any trajectory converges weakly to a minimizer of $\Phi$, and $\Phi(x(t))-\min_{\mathcal H}\Phi = o(t^{-2})$. Strong convergence is established in various practical situations. For the strongly convex case, convergence can be arbitrarily fast depending on the choice of $\alpha$. More precisely, we have $\Phi(x(t))- \min_{\mathcal H}\Phi = \mathcal O(t^{-\frac{2}{3}\alpha})$. We extend the results to the case of a general proper lower-semicontinuous convex function $\Phi : \mathcal H \rightarrow \mathbb R \cup \{+\infty \}$. This is based on the fact that the inertial dynamic with Hessian driven damping can be written as a first-order system in time and space. By explicit-implicit time discretization, this opens a gate to new $-$ possibly more rapid $-$ inertial algorithms, expanding the field of FISTA methods for convex structured optimization problems

Granular Motor in the Non-Brownian Limit

In this work we experimentally study a granular rotor which is similar to the famous Smoluchowski-Feynman device and which consists of a rotor with four vanes immersed in a granular gas. Each side of the vanes can be composed of two different materials, creating a rotational asymmetry and turning the rotor into a ratchet. When the granular temperature is high, the rotor is in movement all the time, and its angular velocity distribution is well described by the Brownian Limit discussed in previous works. When the granular temperature is lowered considerably we enter the so-called Single Kick Limit, where collisions occur rarely and the unavoidable external friction causes the rotor to be at rest for most of the time. We find that the existing models are not capable of adequately describing the experimentally observed distribution in this limit. We trace back this discrepancy to the non-constancy of the deceleration due to external friction and show that incorporating this effect into the existing models leads to full agreement with our experiments. Subsequently, we extend this model to describe the angular velocity distribution of the rotor for any temperature of the gas, and obtain a very good agreement between the model and experimental data

DGR mutagenic transposition occurs via hypermutagenic reverse transcription primed by nicked template RNA.

Diversity-generating retroelements (DGRs) are molecular evolution machines that facilitate microbial adaptation to environmental changes. Hypervariation occurs via a mutagenic retrotransposition process from a template repeat (TR) to a variable repeat (VR) that results in adenine-to-random nucleotide conversions. Here we show that reverse transcription of the Bordetella phage DGR is primed by an adenine residue in TR RNA and is dependent on the DGR-encoded reverse transcriptase (bRT) and accessory variability determinant (Avd ), but is VR-independent. We also find that the catalytic center of bRT plays an essential role in site-specific cleavage of TR RNA for cDNA priming. Adenine-specific mutagenesis occurs during reverse transcription and does not involve dUTP incorporation, indicating it results from bRT-catalyzed misincorporation of standard deoxyribonucleotides. In vivo assays show that this hybrid RNA-cDNA molecule is required for mutagenic transposition, revealing a unique mechanism of DNA hypervariation for microbial adaptation

Adult vitamin D deficiency leads to behavioural and brain neurochemical alterations in C57BL/6J and BALB/c mice

Epidemiological evidence suggests that low levels of vitamin D may predispose people to develop depression and cognitive impairment. While rodent studies have demonstrated that prenatal vitamin D deficiency is associated with altered brain development, there is a lack of research examining adult vitamin D (AVD) deficiency. The aim of this study was to examine the impact of AVD deficiency on behaviour and brain function in the mouse. Ten-week old male C57BL/6J and BALB/c mice were fed a control or vitamin D deficient diet for 10 weeks prior to, and during behavioural testing. We assessed a broad range of behavioural domains, excitatory and inhibitory neurotransmission in brain tissue, and, in separate groups of mice, locomotor response to d-amphetamine and MK-801. Overall, AVD deficiency resulted in hyperlocomotion in a novel open field and reduced GAD65/67 levels in brain tissue. AVD-deficient BALB/c mice had altered behaviour on the elevated plus maze, altered responses to heat, sound and shock, and decreased levels of glutamate and glutamine, and increased levels of GABA and glycine. By contrast C57BL/6J mice had a more subtle phenotype with no further behavioural changes but significant elevations in serine, homovanillic acid and 5-hydroxyindoleacetic acid. Although the behavioural phenotype of AVD did not seem to model a specific disorder, the overall reduction in GAD65/67 levels associated with AVD deficiency may be relevant to a number of neuropsychiatric conditions. This is the first study to show an association between AVD deficiency and prominent changes in behaviour and brain neurochemistry in the mouse