Disease mechanism, biomarker and therapeutics for spinal and bulbar muscular atrophy (SBMA)

Spinal and bulbar muscular atrophy (SBMA) is a hereditary neuromuscular disorder caused by CAG trinucleotide expansion in the gene encoding the androgen receptor (AR). In the central nervous system, lower motor neurons are selectively affected, whereas pathology of patients and animal models also indicates involvement of skeletal muscle including loss of fast-twitch type 2 fibres and increased slow-twitch type 1 fibres, together with a glycolytic-to-oxidative metabolic switch. Evaluation of muscle and fat using MRI, in addition to biochemical indices such as serum creatinine level, are promising biomarkers to track the disease progression. The serum level of creatinine starts to decrease before the onset of muscle weakness, followed by the emergence of hand tremor, a prodromal sign of the disease. Androgen-dependent nuclear accumulation of the polyglutamine-expanded AR is an essential step in the pathogenesis, providing therapeutic opportunities via hormonal manipulation and gene silencing with antisense oligonucleotides. Animal studies also suggest that hyperactivation of Src, alteration of autophagy and a mitochondrial deficit underlie the neuromuscular degeneration in SBMA and provide alternative therapeutic targets

The Mass-Lumped Midpoint Scheme for Computational Micromagnetics: Newton Linearization and Application to Magnetic Skyrmion Dynamics

We discuss a mass-lumped midpoint scheme for the numerical approximation of the Landau-Lifshitz-Gilbert equation, which models the dynamics of the magnetization in ferromagnetic materials. In addition to the classical micromagnetic field contributions, our setting covers the non-standard Dzyaloshinskii-Moriya interaction, which is the essential ingredient for the enucleation and stabilization of magnetic skyrmions. Our analysis also includes the inexact solution of the arising nonlinear systems, for which we discuss both a constraint-preserving fixed-point solver from the literature and a novel approach based on the Newton method. We numerically compare the two linearization techniques and show that the Newton solver leads to a considerably lower number of nonlinear iterations. Moreover, in a numerical study on magnetic skyrmions, we demonstrate that, for magnetization dynamics that are very sensitive to energy perturbations, the midpoint scheme, due to its conservation properties, is superior to the dissipative tangent plane schemes from the literature

Half-Integer Point Defects in the Q-Tensor Theory of Nematic Liquid Crystals

We investigate prototypical profiles of point defects in two dimensional liquid crystals within the framework of Landau-de Gennes theory. Using boundary conditions characteristic of defects of index $k/2$, we find a critical point of the Landau-de Gennes energy that is characterised by a system of ordinary differential equations. In the deep nematic regime, $b^2$ small, we prove that this critical point is the unique global minimiser of the Landau-de Gennes energy. We investigate in greater detail the regime of vanishing elastic constant $L \to 0$, where we obtain three explicit point defect profiles, including the global minimiser.Comment: 15 pages, 16 figure

EZETIMIBE PROTECTS THP-1 CELLS FROM ISCHEMIA-REPERFUSION INJURY REDUCING OXIDATIVE STRESS AND UP-REGULATING NRF2/ ARE GENE EXPRESSION

Background and Aims: We demonstrated that physical training, characterized by repeated ischemia-reperfusion (I-R) episodes (ischemic conditioning, IC), protects circulating cells from peripheral artery disease (PAD) patients against ischemic harms by reducing oxidative stress (OS) and by up-regulating nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway expression. Ezetimibe (Eze) has been shown to alleviate OS enhancing Nrf2 nuclear translocation in an AMPK/p62-dependent manner. In a cellular I-R and IC model, we aimed to investigate: 1) the effect of Eze on OS and Nrf2/ARE gene expression 2) whether Eze could have a synergistic effect on IC. Methods: THP-1 cells were treated with or without Eze (50mM) overnight, then subjected to 1 or 6 repetitive I-R cycles using EVOS FL Auto Imaging System. Reactive oxygen species (ROS) formation was evaluated with DCF in cytofluorimetry. Nrf2/ARE and p62 gene expression were evaluated by RT-PCR and western blotting. Results: When THP-1 cells were exposed to 1 I-R cycle, the preincubation with Eze significantly reduced ROS formation (p<0.01) and up-regulated Nrf2/ARE pathway expression and p62 phosphorylation (p<0.001). Multiple I-R cycles, acting as IC, significantly reduced ROS formation and upregulated Nrf2/ARE gene expression (p<0.001); in these conditions, Eze preincubation was able not only to almost abolish ROS formation (p<0.01) but also further up-regulate Nrf2/ARE expression. Conclusions: In our I-R model, Eze not only restores I-R-induced oxidative damages through Nrf2/ARE signaling up-regulation but also has a synergistic effect on IC. This new \u201cpleiotropic\u201d effect, if confirmed in vivo, may strengthen the use of Eze in PAD patien

A Comparison of Low Read Depth QuantSeq 3 ' Sequencing to Total RNA-Seq in FUS Mutant Mice

Transcriptomics is a developing field with new methods of analysis being produced which may hold advantages in price, accuracy, or information output. QuantSeq is a form of 3′ sequencing produced by Lexogen which aims to obtain similar gene-expression information to RNA-seq with significantly fewer reads, and therefore at a lower cost. QuantSeq is also able to provide information on differential polyadenylation. We applied both QuantSeq at low read depth and total RNA-seq to the same two sets of mouse spinal cord RNAs, each comprised by four controls and four mutants related to the neurodegenerative disease amyotrophic lateral sclerosis. We found substantial differences in which genes were found to be significantly differentially expressed by the two methods. Some of this difference likely due to the difference in number of reads between our QuantSeq and RNA-seq data. Other sources of difference can be explained by the differences in the way the two methods handle genes with different primary transcript lengths and how likely each method is to find a gene to be differentially expressed at different levels of overall gene expression. This work highlights how different methods aiming to assess expression difference can lead to different results

Cannabinoids and their therapeutic applications in mental disorders

Mental disorders represent a significant public health burden worldwide due to their high prevalence, chronically disabling nature, and substantial impact on quality of life. Despite growing knowledge of the pathological mechanisms that underlie the development of these disorders, a high percentage of patients do not respond to first-line clinical treatments; thus, there is a strong need for alternative therapeutic approaches. During the past half-century, after the identification of the endocannabinoid system and its role in multiple physiological processes, both natural and synthetic cannabinoids have attracted considerable interest as putative medications in pathological conditions such as, but not exclusive to, mental disorders. Here, we provide a summary of cannabinoid effects in support of possible therapeutic applications for major depression, bipolar disorder, anxiety, posttraumatic stress disorder, and schizophrenia. Considering this evidence, highlighted benefits and risks of cannabinoid use in the management of these illnesses require further experimental study

Anaplastic Lymphoma Kinase Receptor: Possible Involvement in Anorexia Nervosa

The pathophysiology of Anorexia Nervosa (AN) has not been fully elucidated. Anaplastic lymphoma kinase (ALK) receptor is a protein-tyrosine kinase mainly known as a key oncogenic driver. Recently, a genetic deletion of ALK in mice has been found to increase energy expenditure and confers resistance to obesity in these animals, suggesting its role in the regulation of thinness. Here, we investigated the expression of ALK and the downstream intracellular pathways in female rats subjected to the activity-based anorexia (ABA) model, which reproduces important features of human AN. In the hypothalamic lysates of ABA rats, we found a reduction in ALK receptor expression, a downregulation of Akt phosphorylation, and no change in the extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) phosphorylation. After the recovery from body weight loss, ALK receptor expression returned to the control baseline values, while it was again suppressed during a second cycle of ABA induction. Overall, this evidence suggests a possible involvement of the ALK receptor in the pathophysiology of AN, that may be implicated in its stabilization, resistance, and/or its exacerbation

Spectroscopic follow-up of a subset of the Gaia/IPHAS catalogue of Hα-excess sources

State-of-the-art techniques to identify Hα emission-line sources in narrow-band photometric surveys consist of searching for  Hα excess with reference to nearby objects in the sky (position-based selection). However, while this approach usually yields very few spurious detections, it may fail to select intrinsically faint and/or rare Hα-excess sources. In order to obtain a more complete representation of the heterogeneous emission-line populations, we recently developed a technique to find outliers relative to nearby objects in the colour–magnitude diagram (CMD-based selection). By combining position-based and CMD-based selections, we built an updated catalogue of Hα-excess candidates in the Northern Galactic Plane. Here, we present spectroscopic follow-up observations and classification of 114 objects from this catalogue that enables us to test our novel selection method. Out of the 70 spectroscopically confirmed Hα-emitters in our sample, 15 were identified only by the CMD-based selection, and would have been thus missed by the classic position-based technique. In addition, we explore the distribution of our spectroscopically confirmed emitters in the Gaia CMD. This information can support the classification of emission-line sources in large surveys such as the upcoming WEAVE and 4-m Multi-Object Spectroscopic Telescope, especially if augmented with the introduction of other colours

A note on boundedness of operators in Grand Grand Morrey spaces

In this note we introduce grand grand Morrey spaces, in the spirit of the grand Lebesgue spaces. We prove a kind of \textit{reduction lemma} which is applicable to a variety of operators to reduce their boundedness in grand grand Morrey spaces to the corresponding boundedness in Morrey spaces. As a result of this application, we obtain the boundedness of the Hardy-Littlewood maximal operator and Calder\'on-Zygmund operators in the framework of grand grand Morrey spaces.Comment: 8 page