INTRODUCTION
Genetic studies conducted over the past four decades have provided us with a detailed catalog of genes that play critical roles in the etiology of Alzheimer's disease (AD) and related ...dementias (ADRDs). Despite this progress, as a field we have had only limited success in incorporating this rich complexity of human AD/ADRD genetics findings into our animal models of these diseases. Our primary goal for the gene replacement (GR)‐AD project is to develop mouse lines that model the genetics of AD/ADRD as closely as possible.
METHODS
To do this, we are generating mouse lines in which the genes of interest are precisely and completely replaced in the mouse genome by their full human orthologs.
RESULTS
Each model set consists of a control line with a wild‐type human allele and variant lines that precisely match the human genomic sequence in the control line except for a high‐impact pathogenic mutation or risk variant.
Abstract
In this paper, we discuss the effects of nonlinear electrodynamics (NED) on non-rotating black holes, parametrized by the field coupling parameter β and magnetic charge parameter P in ...detail. Particularly, we survey a large range of observables and physical properties of the magnetically charged black hole, including the thermodynamic properties, observational appearance, quasinormal modes and absorption cross sections. Initially, we show that the NED black hole is always surrounded by an event horizon and any magnetic charge is permissible. We then show that the black hole gets colder with increasing charge. Investigating the heat capacity, we see that the black hole is thermally stable between points of phase transition. Introducing a generalized uncertainty principle (GUP) with a quantum gravity parameter λ extends the range of the stable region, but the effect on temperature is negligible. Then we compute the deflection angle at the weak field limit, by the Gauss-Bonnet theorem and the geodesic equation, and find that even at the first order, the magnetic charge has a contribution due to the “field mass” term. Small changes of the charge contributes greatly to the paths of null geodesics due to the
P
2
dependence of the horizon radius. Using a ray-tracing code, we simulate the observational appearance of a NED black hole under different emission profiles, thin disk and spherical accretion. We find that the parameter
P
has a very strong effect on the observed shadow radius, in agreement with the deflection angle calculations. We finally consider quasinormal modes under massless scalar perturbations of the black hole and the greybody factor. We find that the charge introduces a slight difference in the fundamental frequency of the emitted waveform. We find that the greybody factor of the NED black hole is strongly steepened by the introduction of increasing charge. To present observational constrains, we show that the magnetic charge of the M87
*
black hole is between 0 ≤
P
≤ 0.024 in units of M, in agreement with the idea that real astrophysical black holes are mostly neutral. We also find that LIGO/VIRGO and LISA could detect NED black hole perturbations from BHs with masses between 5
M
☉
and 8.0 · 10
8
M
☉
. We finally show that for black holes with masses detected with LIGO so far, charged NED black holes would deviate from Schwarzschild by 5∼10 Hz in their fundamental frequencies.
ABSTRACT
The circadian clock is a critical regulator of immune function. We recently highlighted a role for the circadian clock in a mouse model of pulmonary inflammation. The epithelial clock ...protein Bmal1 was required to regulate neutrophil recruitment in response to inflammatory challenge. Bmal1 regulated glucocorticoid receptor (GR) recruitment to the neutrophil chemokine, CXC chemokine ligand 5 (CXCL5), providing a candidate mechanism. We now show that clock control of pulmonary neutrophilia persists without rhythmic glucocorticoid availability. Epithelial GR‐null mice had elevated expression of proinflammatory chemokines in the lung under homeostatic conditions. However, deletion of GR in the bronchial epithelium blocked rhythmic CXCL5 production, identifying GR as required to confer circadian control to CXCL5. Surprisingly, rhythmic pulmonary neutrophilia persisted, despite nonrhythmic CXCL5 responses, indicating additional circadian control mechanisms. Deletion of GR in myeloid cells alone did not prevent circadian variation in pulmonary neutrophilia and showed reduced neutrophilic inflammation in response to dexamethasone treatment. These new data show GR is required to confer circadian control to some inflammatory chemokines, but that this alone is insufficient to prevent circadian control of neutrophilic inflammation in response to inhaled LPS, with additional control mechanisms arising in the myeloid cell lineage.—Ince, L. M., Zhang, Z., Beesley, S., Vonslow, R. M., Saer, B. R., Matthews, L. C., Begley, N., Gibbs, J. E., Ray, D. W., Loudon, A. S. I. Circadian variation in pulmonary inflammatory responses is independent of rhythmic glucocorticoid signaling in airway epithelial cells. FASEB J. 33, 126–139 (2019). www.fasebj.org
Heat shock protein 90 (Hsp90) is an ATP-dependent molecular chaperone which is essential in eukaryotes. It is required for the activation and stabilization of a wide variety of client proteins and ...many of them are involved in important cellular pathways. Since Hsp90 affects numerous physiological processes such as signal transduction, intracellular transport, and protein degradation, it became an interesting target for cancer therapy. Structurally, Hsp90 is a flexible dimeric protein composed of three different domains which adopt structurally distinct conformations. ATP binding triggers directionality in these conformational changes and leads to a more compact state. To achieve its function, Hsp90 works together with a large group of cofactors, termed co-chaperones. Co-chaperones form defined binary or ternary complexes with Hsp90, which facilitate the maturation of client proteins. In addition, posttranslational modifications of Hsp90, such as phosphorylation and acetylation, provide another level of regulation. They influence the conformational cycle, co-chaperone interaction, and inter-domain communications. In this review, we discuss the recent progress made in understanding the Hsp90 machinery.
Abstract
In the context of the metric-affine Chern-Simons gravity endowed with projective invariance, we derive analytical solutions for torsion and nonmetricity in the homogeneous and isotropic ...cosmological case, described by a flat Friedmann-Robertson-Walker metric. We discuss in some details the general properties of the cosmological solutions in the presence of a perfect fluid, such as the dynamical stability and the emergence of big bounce points, and we examine the structure of some specific solutions reproducing de Sitter and power law behaviours for the scale factor. Then, we focus on first-order perturbations in the de Sitter scenario, and we study the propagation of gravitational waves in the adiabatic limit, looking at tensor and scalar polarizations. In particular, we find that metric tensor modes couple to torsion tensor components, leading to the appearance, as in the metric version of Chern-Simons gravity, of birefringence, characterized by different dispersion relations for the left and right circularized polarization states. As a result, the purely tensor part of torsion propagates like a wave, while nonmetricity decouples and behaves like a harmonic oscillator. Finally, we discuss scalar modes, outlining as they decay exponentially in time and do not propagate.
This Special Issue reprint aims to collect new or improved ideas to exploit superconducting materials, as well as graphene, towards achieving innovative devices, either at a small scale, as well as ...at a large scale. Several potential applications of graphene are enhanced by the possibility to modify its surface to introduce a non-zero bandgap, to tune adhesion and/or hydrophobicity/hydrophilicity, etc. These surface properties are crucial to the realization of graphene-based devices. Papers demonstrating graphene and/or superconducting devices, device processing, characterization, and applications, are particularly welcomed. Topics in this Special Issue include, but are not limited to: Graphene devices Graphene based heterostructures Superconducting interfaces Superconducting devices Electronic, optical, photonic and magnetic properties Surface and interfacial characterization techniques Device integration and fabrication
Abstract
In this note, we present a synopsis of geometric symmetries for (spin 0) perturbations around (4D) black holes and de Sitter space. For black holes, we focus on static perturbations, for ...which the (exact) geometric symmetries have the group structure of
SO(1,3). The generators consist of three spatial rotations, and three conformal Killing vectors obeying a special
melodic
condition. The static perturbation solutions form a unitary (principal series) representation of the group. The recently uncovered ladder symmetries follow from this representation structure; they explain the well-known vanishing of the black hole Love numbers. For dynamical perturbations around de Sitter space, the geometric symmetries are less surprising, following from the SO(1,4) isometry. As is known, the quasinormal solutions form a non-unitary representation of the isometry group. We provide explicit expressions for the ladder operators associated with this representation. In both cases, the ladder structures help connect the boundary condition at the horizon with that at infinity (black hole) or origin (de Sitter space), and they manifest as contiguous relations of the hypergeometric solutions.
Acute myelitis (AM) is a rare neuro‐immune spinal cord disease. This study sought to explore the transcription level of glucocorticoid (GC) receptors α and β (GR‐α/GR‐β) in peripheral blood ...mononuclear cells (PBMCs) and their correlation with GC efficacy and sensitivity in AM patients. AM patients were grouped into the GC‐sensitive group (N = 80) and GC‐refractory group (N = 67). The GR‐α and GR‐β mRNA levels in PBMCs were detected. The differentiating value of GR‐α, GR‐β, and GR‐α + GR‐β on GC sensitivity and resistance in AM patients was assessed. The independent correlation between GR‐α and GR‐β mRNA levels and GC sensitivity in AM patients,t and the correlation between GR‐α and GR‐β mRNA levels and spinal function after GC treatment were analyzed. GR‐α mRNA level in PBMCs of GC‐refractory patients was lower than that of GC‐sensitive patients, while GR‐β mRNA level was higher than that of GC‐sensitive patients. GR‐α + GR‐β mRNA had a high diagnostic value for GC sensitivity and resistance in AM patients (area under the ROC curve = 0.881, sensitivity = 79.1%, specificity = 85.0%). GR‐α and GR‐β mRNA levels were independently correlated with GC sensitivity. GR‐α and GR‐β mRNA levels were correlated with the spinal function of AM patients after GC treatment. Overall, GR‐α and GR‐β mRNA levels in PBMCs of AM patients can assist in the identification of GC sensitivity and are correlated with GC efficacy.
Abstract We examine the motion of the massless scalar field and nearly bound null geodesics in the near-ring region of a black hole, which may possess either acceleration or a gravitomagnetic mass. ...Around such black holes, the photon ring deviates from the equatorial plane. In the large angular momentum limit, we demonstrate that the massless scalar field exhibits an emergent conformal symmetry in this near-ring region. Additionally, in the nearly bound limit, we observe the emergence of a conformal symmetry for the null geodesics that constitute the photon ring in the black hole image. These findings suggest that the hidden conformal symmetry, associated with the Lie algebra (2, ℝ), persists even for black holes lacking north-south reflection symmetry, thereby broadening the foundation of photon ring holography. Finally, we show that the conformal symmetry also emerges for nearly bound timelike geodesics and scalar fields in proximity to the particle ring, and with specific mass around a Schwarzschild black hole.
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