Degenerate Conditions Research Articles

Drug Discovery Strategies for Inherited Retinal Degenerations.

Simple SummaryInherited retinal degeneration is a group of heterogeneous genetic disorders impairing vision. In these diseases, photoreceptor or retinal ganglion cells become dysfunctional and degenerate. Currently, no cures exist for these devastating blinding conditions. In this review, we will discuss targets and drug discovery strategies for inherited retinal degeneration using animal models, stem cells, and small molecule screening with updates on preclinical developments.Inherited retinal degeneration is a group of blinding disorders afflicting more than 1 in 4000 worldwide. These disorders frequently cause the death of photoreceptor cells or retinal ganglion cells. In a subset of these disorders, photoreceptor cell death is a secondary consequence of retinal pigment epithelial cell dysfunction or degeneration. This manuscript reviews current efforts in identifying targets and developing small molecule-based therapies for these devastating neuronal degenerations, for which no cures exist. Photoreceptors and retinal ganglion cells are metabolically demanding owing to their unique structures and functional properties. Modulations of metabolic pathways, which are disrupted in most inherited retinal degenerations, serve as promising therapeutic strategies. In monogenic disorders, great insights were previously obtained regarding targets associated with the defective pathways, including phototransduction, visual cycle, and mitophagy. In addition to these target-based drug discoveries, we will discuss how phenotypic screening can be harnessed to discover beneficial molecules without prior knowledge of their mechanisms of action. Because of major anatomical and biological differences, it has frequently been challenging to model human inherited retinal degeneration conditions using small animals such as rodents. Recent advances in stem cell-based techniques are opening new avenues to obtain pure populations of human retinal ganglion cells and retinal organoids with photoreceptor cells. We will discuss concurrent ideas of utilizing stem-cell-based disease models for drug discovery and preclinical development.

Location of singular points in orthorhombic media

The dependence of the location of singular points of orthorhombic (ORT) media on the stiffness coefficients , and phase velocity at the singularity point is studied under the assumption that are larger than and . In this case, singular points appear only at the intersection of slowness surfaces of S1- and S2-waves. To simplify the presentation of the results, the values , are fixed and changed within the limits at which the stiffness matrix remains positive definite. We define the parameters, , , , which result in 0, 1, or 2 singular points in the symmetry planes of the ORT medium. The types of these singular points and their location on the unit circle are described. It is shown that, by selecting parameters , any singular point in the symmetry plane 13 can be combined with the limiting position of the singularity point in-between the symmetry planes, or this point can be included in the singular curve of the degenerate ORT medium. We derive equations for the semi-axes of an ellipse of conical refraction, which is the image of a singular point from plane 13 in the group domain. Conditions for degeneration of the ellipse of conical refraction into a segment or a point are defined. It is shown that there exists only one ORT medium with a fixed phase velocity of S1- and S2-waves in a given singular direction n. If we present the ORT media as projections of these vectors n onto the plane 12 and mark the value of the Poincaré index of the S1- or S2-wave at the point n, we get 2 regions with indices 1/2 and –1/2 separated by projection of the singular curve in the form of an ellipse or hyperbola. We compute equations for of a degenerate ORT medium in terms of the values, , and velocity of S1-, S2-waves on a singular curve. The singular curve is defined by the intersection of a unit sphere with an elliptic cone. It is proved that a degenerate ORT medium for or is, respectively, a transversally isotropic medium with a vertical or horizontal axis of symmetry. The results are illustrated in several examples.

Retinal neurodegeneration in a mouse model of green-light-induced myopia

PurposeTo determine the retinal neurodegeneration occurring in mice with green-light-induced myopia. MethodsFour-week-old mice were raised under white or green light (peak at 510 nm). Refraction and axial length (AL) were measured before and after eight weeks of illumination treatment. TUNEL staining, electron microscopy and the Visual Cliff test were performed to identify the conditions of retinal degeneration. The distinct protein signatures of retina tissues were quantified by mass spectrometry (MS) - based proteomics, and analyzed by Gene Set Enrichment Analysis (GSEA), Kyoto Encyclopedia of Genes and Genomes (KEGG) annotation and STRING database. Western blot was used to detect the expression of the specific protein. ResultsGreen-light-induced myopia was developed in mice after eight weeks of illumination treatment. Apoptosis and the abnormality in ultrastructure and visual function of mice exposed to green light were found through morphological and behavioral experiment, indicating retinal degeneration. The altered proteome was associated with Human Phenotype Ontology (HPO) annotations sets of ‘abnormality of visual evoked potentials’ and ‘neuronal loss in central nervous system’. KEGG annotation demonstrated the altered pathway of the dopaminergic synapse in the myopic mice. STRING database was utilized with an effort to identify the molecular pathways within, and dysregulation of mitochondrial metabolism was revealed. ConclusionsOverall, our study revealed molecular differences and pathways underlying retinal degeneration in the mouse model of green-light-induced myopia. These findings might provide insights into further research into myopia prevention and control.

MS2Net: Multi-Scale and Multi-Stage Feature Fusion for Blurred Image Super-Resolution

At present, most mainstream algorithms for single image super-resolution (SISR) assume the image degradation process as an ideal degradation process (e.g. bicubic downscaling), which violates the actual degeneration conditions. In real-world image capturing, objects often move in a dynamic environment, and camera shake also often occurs, which results in serious blurs. Our work focuses on the task of image super-resolution with heavy motion blur, for which we adopt a network with two branches: one branch for image deblurring and the other one for super-resolution. Since the features obtained by the deblurring are rich in details, we apply their features as supplementary information to the super-resolution branch. Based on the adopted dual-branch framework, our major technical novelties lie in two novel modules: Multi-Scale Feature Fusion (MSFF1) module which fuses features of different scale from the deblurring branch to get local and global information, and Multi-Stage Feature Fusion (MSFF2) module which further filters useful information with attention. We evaluate the proposed method under various blur scenarios on the benchmark datasets, demonstrating competitive performance against existing methods.

Conservation of Total Wave Action in the Expanding Solar Wind

The conservation of wave action in moving plasmas has been well known for over half a century. However, wave action is not conserved when multiple wave modes propagate and coexist close to the degeneration condition (where the sound speed equals the Alfvén speed, i.e., plasma β ∼ 1). Here, we show that the violation of conservation is due to wave mode conversion, and that the total wave action summed over the interacting modes is still conserved. Though the result is general, we focus on MHD waves and identify three distinctive mode-conversion mechanisms, i.e., degeneracy, linear mode conversion, and resonance, and provide an intuitive physical picture for the mode-conversion processes. We use one-dimensional MHD simulations with the Expanding Box Model to simulate the nonlinear evolution of monochromatic MHD waves in the expanding solar wind. The simulation results validate the theory; total wave action therefore remains an interesting diagnostic for studies of waves and turbulence in the solar wind.

20 Puntos clave para entender la mortífera decadencia del capitalismo

Since 2008, at the International Crisis Observatory, we have been working on the recurring structural crises of capitalism, their profound reasons, in order to be able to specify and explain its current systemic quagmire, which for us is nothing more than a symptom of its degenerative phase (“senile capitalism” Amin called it), tenden-tially terminal, without “terminal” necessarily meaning “imminent”. To locate ourselves in this trend, it is necessary to show that the conditions of degeneration are becoming more acute and that the development of the productive forces increasingly gives way to destructive forces, with the consequent decline of the whole of capitalist civilization. Dilution of value, social and environmental destruction, collapse of societies... In this article I intend to expose in the clearest and simplest way possible some of the processes that explain all this, as well as the conclusions or implications that are attached to them. I will do it in 20 points, for whose greater depth and exposition of data I have to refer at least to some of my previous works on the matter (Piqueras, 2014, 2017a, 2017b, 2018 and 2022, with its corresponding bibliography – and also that of the rest of the team-). I try to synthesize, in the most didactic way possible, some of the most relevant processes and factors for the analysis of the current phase of capitalism. En este artículo se analizan las tendencias autodestructivas del capitalismo así como sus consecuencias y los desórdenes mundiales de su decadencia. Piqueras realiza una detallada exposición de los factores perturbadores más relevantes de este fenómeno: desde la caída de la tasa de ganancia, el descenso de la productividad o el agotamiento irracional de los recursos naturales, hasta la acumulación bélica de capital, el último desplazamiento de un sistema visiblemente agotado.

Tadpole cosmology: self tuning without degeneracy

Degeneracy is a method to accommodate exact, low energy vacuum states in scalar-tensor gravitational models despite the presence of an arbitrarily large vacuum energy. However, this approach requires very particular combinations of scalar field and metric couplings in the Lagrangian. In this work we study departures from the restrictive degeneracy condition — starting from a fiducial model containing an exact Minkowski space solution, we break the degeneracy condition in numerous simple ways to test if the resulting models maintain certain key features — specifically the dynamical cancellation of a large vacuum energy by the scalar field and the existence of a low energy vacuum state. We highlight the role the tadpole plays in eliminating the fixed points of the dynamical system, generically rendering both the scalar field and metric time dependent. Our results indicate that when violating the degeneracy condition but preserving shift symmetry, the metric maintains an asymptotic Minkowski state, irrespective of the presence of the cosmological constant. In contrast, when shift symmetry is also broken the asymptotic behaviour can radically alter. Regardless, the non-degenerate models in this work share an attractive quality; harboring low energy, late-time asymptotic states that are independent of the vacuum energy. The tadpole allows for a broader class of non-degenerate, self-tuning models than was previously realized.

Existence of Hölder Continuous Solutions for a Class of Degenerate Fourth-Order Elliptic Equations

This paper deals with the existence of bounded and locally Hölder continuous weak solutions of a homogeneous Dirichlet problem related to a class of nonlinear fourth-order elliptic equations with strengthened degenerate ellipticity condition.

Photonic topological semimetals in bigyrotropic metamaterials

We investigate the photonic topological phases in bigyrotropic metamaterials characterized by the gyroelectric and gyromagnetic parameters. The underlying medium is considered a photonic analogue of the topological semimetal featured with a pair of Weyl cones separated by a distance in the frequency-wave vector space. As the 'spin'-degenerate condition is satisfied, the photonic system consists of two hybrid modes that are completely decoupled. By introducing the pseudospin states as the basis for the hybrid modes, the photonic system is described by two subsystems in terms of the spin-orbit Hamiltonians with spin 1, which result in nonzero spin Chern numbers that determine the topological properties. Surface modes at the interface between two bigyrotropic metamaterials with opposite sign of the gyrotropic parameters exist in their common gap in the wave vector space, which are analytically formulated by algebraic equations. In particular, two types of surface modes are tangent to or wrapping around the Weyl cones, which form a bent and two twisted surface sheets. At the Weyl frequency, the surface modes contain a typical and two open Fermi arc-like states that concatenate to yield an infinite straight line. Topological features of the bigyrotropic metamaterials are further illustrated with the robust transport of surface modes at an irregular boundary.

Flexible list colorings in graphs with special degeneracy conditions

AbstractFor a given , we say that a graph is ‐flexibly ‐choosable if the following holds: for any assignment of color lists of size on , if a preferred color from a list is requested at any set of vertices, then at least of these requests are satisfied by some ‐coloring. We consider the question of flexible choosability in several graph classes with certain degeneracy conditions. We characterize the graphs of maximum degree that are ‐flexibly ‐choosable for some , which answers a question of Dvořák Norin, and Postle [List coloring with requests, JGT 2019]. In particular, we show that for any , any graph of maximum degree that is not isomorphic to is ‐flexibly ‐choosable. Our fraction of is within a constant factor of being the best possible. We also show that graphs of treewidth 2 are ‐flexibly 3‐choosable, answering a question of Choi et al. [Flexibility of planar graphs‐sharpening the tools to get lists of size four, DAM 2022], and we give conditions for list assignments by which graphs of treewidth are ‐flexibly ‐choosable. We show furthermore that graphs of treedepth are ‐flexibly ‐choosable. Finally, we introduce a notion of flexible degeneracy, which strengthens flexible choosability, and we show that apart from a well‐understood class of exceptions, 3‐connected nonregular graphs of maximum degree are flexibly ‐degenerate.

GFINNs: GENERIC formalism informed neural networks for deterministic and stochastic dynamical systems.

We propose the GENERIC formalism informed neural networks (GFINNs) that obey the symmetric degeneracy conditions of the GENERIC formalism. GFINNs comprise two modules, each of which contains two components. We model each component using a neural network whose architecture is designed to satisfy the required conditions. The component-wise architecture design provides flexible ways of leveraging available physics information into neural networks. We prove theoretically that GFINNs are sufficiently expressive to learn the underlying equations, hence establishing the universal approximation theorem. We demonstrate the performance of GFINNs in three simulation problems: gas containers exchanging heat and volume, thermoelastic double pendulum and the Langevin dynamics. In all the examples, GFINNs outperform existing methods, hence demonstrating good accuracy in predictions for both deterministic and stochastic systems. This article is part of the theme issue 'Data-driven prediction in dynamical systems'.

Inverted conical methane/air flame shape transformation under acoustic excitation: Gravity impact

In this paper it is shown that under certain conditions under reverse gravity, acoustics increase the stability of the flame in comparison with normal gravity. It is shown that there is a hysteresis in the V–M and M–V transitions under reverse gravity as well as under normal one. In contrast to normal gravity, the conditions for hysteresis degeneracy under reverse gravity are proven to be independent of the excitation frequency.

Robust Connectivity of Graphs on Surfaces

Let $\Lambda(T)$ denote the set of leaves in a tree $T$. One natural problem is to look for a spanning tree $T$ of a given graph $G$ such that $\Lambda(T)$ is as large as possible. This problem is called maximum leaf number, and it is a well-known NP-hard problem. Throughout recent decades, this problem has received considerable attention, ranging from pure graph theoretic questions to practical problems related to the construction of wireless networks. Recently, a similar but stronger notion was defined by Bradshaw, Masa\v{r}\'ik, and Stacho [Flexible List Colorings in Graphs with Special Degeneracy Conditions, ISAAC 2020]. They introduced a new invariant for a graph $G$, called the robust connectivity and written $\kappa_\rho(G)$, defined as the minimum value $\frac{|R \cap \Lambda (T)|}{|R|}$ taken over all nonempty subsets $R\subseteq V(G)$, where $T = T(R)$ is a spanning tree on $G$ chosen to maximize $|R \cap \Lambda(T)|$. Large robust connectivity was originally used to show flexible choosability in non-regular graphs. In this paper, we investigate some interesting properties of robust connectivity for graphs embedded in surfaces. We prove a tight asymptotic bound of $\Omega(\gamma^{-\frac{1}{r}})$ for the robust connectivity of $r$-connected graphs of Euler genus $\gamma$. Moreover, we give a surprising connection between the robust connectivity of graphs with an edge-maximal embedding in a surface and the surface connectivity of that surface, which describes to what extent large induced subgraphs of embedded graphs can be cut out from the surface without splitting the surface into multiple parts. For planar graphs, this connection provides an equivalent formulation of a long-standing conjecture of Albertson and Berman [A conjecture on planar graphs, 1979], which states that every planar graph on $n$ vertices contains an induced forest of size at least $n/2$.

Longitudinal RNA Sequencing of Skin and DRG Neurons in Mice with Paclitaxel-Induced Peripheral Neuropathy.

Paclitaxel-induced peripheral neuropathy is a condition of nerve degeneration induced by chemotherapy, which afflicts up to 70% of treated patients. Therapeutic interventions are unavailable due to an incomplete understanding of the underlying mechanisms. We previously discovered that major physiological changes in the skin underlie paclitaxel-induced peripheral neuropathy in zebrafish and rodents. The precise molecular mechanisms are only incompletely understood. For instance, paclitaxel induces the upregulation of MMP-13, which, when inhibited, prevents axon degeneration. To better understand other gene regulatory changes induced by paclitaxel, we induced peripheral neuropathy in mice following intraperitoneal injection either with vehicle or paclitaxel every other day four times total. Skin and dorsal root ganglion neurons were collected based on distinct behavioural responses categorised as “pain onset” (d4), “maximal pain” (d7), “beginning of pain resolution” (d11), and “recovery phase” (d23) for comparative longitudinal RNA sequencing. The generated datasets validate previous discoveries and reveal additional gene expression changes that warrant further validation with the goal to aid in the development of drugs that prevent or reverse paclitaxel-induced peripheral neuropathy.

The effect of age-related macular degeneration on cognitive test performance

The reliable assessment of cognitive functioning is critical to the study of brain-behaviour relationships. Yet conditions that are synchronous which ageing, including visual decline, are easily overlooked when interpreting cognitive test scores. The purpose of this study was to demonstrate the negative consequences of visual impairments on cognitive tests performance. Moderate to severe levels of age-related macular degeneration were simulated, with a set of goggles, in a sample of twenty-four normally sighted participants while they completed two cognitive tasks: a vision-dependent reaction time task and a vision-independent verbal fluency test. Performance on the reaction time task significantly decreased (p < 0.001) in the simulated age-related macular degeneration condition, by as much as 25 percentile ranks. In contrast, performance on the verbal fluency test were not statistically different between the simulated and normal vision conditions (p = 0.78). The findings highlight the importance of considering visual functioning when assessing cognitive function. When vision is not accounted for, low test scores may inaccurately indicate poor cognition. Such false attributions may have significant ramification for diagnosis and research on cognitive functioning.

Higher derivative scalar tensor theory in unitary gauge

Ostrogradsky instability generally appears in nondegenerate higher-order derivative theories and this issue can be resolved by removing any existing degeneracy present in such theories. We consider an action involving terms that are at most quadratic in second derivatives of the scalar field and non-minimally coupled with the curvature tensors. We perform a 3+1 decomposition of the Lagrangian to separate second-order time derivative terms from rest. This decomposition is useful for checking the degeneracy hidden in the Lagrangian and helps us find conditions under which Ostrogradsky instability does not appear. We show that our construction of Lagrangian resembles that of a GR-like theory for a particular case in the unitary gauge. As an example, we calculate the equation of motion for the flat FRW. We also write the action for open and closed cases, free from higher derivatives for a particular choice derived from imposing degeneracy conditions.

Melanocortin receptor agonists suppress experimental autoimmune uveitis

The melanocortin system plays an essential role in the regulation of immune activity. The anti-inflammatory microenvironment of the eye is dependent on the expression of the melanocortin-neuropeptide alpha-melanocyte stimulating hormone (α-MSH). In addition, the melanocortin system may have a role in retinal development and retinal cell survival under conditions of retinal degeneration. We have found that treating experimental autoimmune uveitis (EAU) with α-MSH suppresses retinal inflammation. Also, this augmentation of the melanocortin system promotes immune tolerance and protection of the retinal structure. The benefit of α-MSH-therapy appears to be dependent on different melanocortin receptors. Therefore, we treated EAU mice with α-MSH-analogs with different melanocortin-receptor targets. This approach demonstrated which melanocortin-receptors suppress inflammation, preserve retinal structure, and induce immune tolerance in uveitis. At the chronic stage of EAU the mice were injected twice 1 day apart with 50 μg of α-MSH or an α-MSH-analog. The α-MSH-analogs were a pan-agonist PL8331, PL8177 (potent MC1r-only agonist), PL5000 (a pan-agonist with no MC5r functional activity), MT-II (same as PL5000) and PG901 (MC5r agonist, but also an antagonist to MC3r, and MC4r). Clinical EAU scores were measured until resolution in the α-MSH-treated mice, when the eyes were collected for histology, and spleen cells collected for retinal-antigen-stimulated cytokine production. Significant suppression of EAU was seen with α-MSH or PL8331 treatment. This was accompanied with significant preservation of retinal structure. A similar effect was seen in EAU-mice that were treated with PL8177, except the suppression of EAU was temporary. In EAU mice treated with PL5000, MTII, or PG901, there was no suppression of EAU with a significant loss in whole retina and outer-nuclear layer thickness. There was significant suppression of IL-17 with induction of IL-10 by retinal-antigen stimulated spleen T cells from EAU mice treated with α-MSH, PL8331, PL8177, or PL5000, but not from EAU mice treated with MT-II, or PG901. Our previous studies show the melanocortin system's importance in maintaining ocular immune privilege and that α-MSH-treatment accelerates recovery and induces retinal-antigen-specific regulatory immunity in EAU. Our current results show that this activity is centered around MC1r and MC5r. In addition, the results suggest that a therapeutic potential to target MC1r and MC5r together to suppress uveitis induces regulatory immunity with potentially maintaining a normal retinal structure.

Covariant 3+1 correspondence of the spatially covariant gravity and the degeneracy conditions

A necessary condition for a generally covariant scalar-tensor theory to be ghostfree is that it contains no extra degrees of freedom in the unitary gauge, in which the Lagrangian corresponds to the spatially covariant gravity. Compared with analyzing the scalar-tensor theory directly, it is simpler to map the spatially covariant gravity to the generally covariant scalar-tensor theory using the gauge recovering procedures. In order to ensure the resulting scalar-tensor theory to be ghostfree absolutely, i.e., no matter if the unitary gauge is accessible, a further covariant degeneracy/constraint analysis is required. We develop a method of covariant $3+1$ correspondence, which maps the spatially covariant gravity to the scalar-tensor theory in $3+1$ decomposed form without fixing any coordinates. Then the degeneracy conditions to remove the extra degrees of freedom can be found easily. As an illustration of this approach, we show how the Horndeski theory is recovered from the spatially covariant gravity. This approach can be used to find more general ghostfree scalar-tensor theory.

MORPHIOUS: an unsupervised machine learning workflow to detect the activation of microglia and astrocytes

BackgroundIn conditions of brain injury and degeneration, defining microglial and astrocytic activation using cellular markers alone remains a challenging task. We developed the MORPHIOUS software package, an unsupervised machine learning workflow which can learn the morphologies of non-activated astrocytes and microglia, and from this information, infer clusters of microglial and astrocytic activation in brain tissue.MethodsMORPHIOUS combines a one-class support vector machine with the density-based spatial clustering of applications with noise (DBSCAN) algorithm to identify clusters of microglial and astrocytic activation. Here, activation was triggered by permeabilizing the blood–brain barrier (BBB) in the mouse hippocampus using focused ultrasound (FUS). At 7 day post-treatment, MORPHIOUS was applied to evaluate microglial and astrocytic activation in histological tissue. MORPHIOUS was further evaluated on hippocampal sections of TgCRND8 mice, a model of amyloidosis that is prone to microglial and astrocytic activation.ResultsMORPHIOUS defined two classes of microglia, termed focal and proximal, that are spatially adjacent to the activating stimulus. Focal and proximal microglia demonstrated activity-associated features, including increased levels of ionized calcium-binding adapter molecule 1 expression, enlarged soma size, and deramification. MORPHIOUS further identified clusters of astrocytes characterized by activity-related changes in glial fibrillary acidic protein expression and branching. To validate these classifications following FUS, co-localization with activation markers were assessed. Focal and proximal microglia co-localized with the transforming growth factor beta 1, while proximal astrocytes co-localized with Nestin. In TgCRND8 mice, microglial and astrocytic activation clusters were found to correlate with amyloid-β plaque load. Thus, by only referencing control microglial and astrocytic morphologies, MORPHIOUS identified regions of interest corresponding to microglial and astrocytic activation.ConclusionsOverall, our algorithm is a reliable and sensitive method for characterizing microglial and astrocytic activation following FUS-induced BBB permeability and in animal models of neurodegeneration.

Quantum stability of a new Proca theory

The construction of general derivative self-interactions for a massive Proca field relies on the well-known condition for constrained systems of having a degenerate Hessian. The nature of the existing constraints algebra will distinguish among different classes of interactions. Proca-Nuevo interactions enjoy a non-trivial constraint by mixing terms of various order whereas Generalized Proca interactions satisfy the degeneracy condition order by order for each individual Lagrangians. In both cases the vector field propagates at most three degrees of freedom. It has been shown that the scattering amplitudes of Proca-Nuevo arising at the tree level always differ from those of the Generalized Proca, implying their genuinely different nature and a lack of relation by local field redefinitions. In this work, we show the quantum stability of the Proca-Nuevo theory below a specific UV cut-off. Although Proca-Nuevo and Generalized Proca are different inherently in their classical structure, both have the same high energy behaviour when quantum corrections are taken into account. The arising counter terms have the exact same structure and scaling. This might indicate that whatever UV completion they may come from, we expect it to be of similar nature.