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
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.
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
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.
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