EZH2 inhibition stimulates repetitive element expression and viral mimicry in resting splenic B cells.

Mammalian cells repress expression of repetitive genomic sequences by forming heterochromatin. However, the consequences of ectopic repeat expression remain unclear. Here we demonstrate that inhibitors of EZH2, the catalytic subunit of the Polycomb repressive complex 2 (PRC2), stimulate repeat misexpression and cell death in resting splenic B cells.

The effect of HLA-DRB1*04:01 on a mouse model of atherosclerosis.

Objectives: HLA-DRB1 is associated with an increased risk of cardiovascular disease in patients with rheumatoid arthritis (RA). This study aimed to determine the effect of HLA-DRB1 on atherosclerotic cardiovascular disease (ASCVD) using a novel mouse model.

Methods: Mice transgenic for HLA-DRB1*04:01 (DR4tg) were crossed with low density lipoprotein receptor knock-out () mice that develop atherosclerosis when fed a high fat, high cholesterol (HFHC) diet.

Deletion of Dysregulates ERK and STAT3 Activity in Mouse Embryonic Stem Cells, Enhancing Their Naive-Like Self-Renewal in the Presence of Leukemia Inhibitory Factor.

The ShcA adapter protein is necessary for early embryonic development. The role of ShcA in development is primarily attributed to its 52 and 46 kDa isoforms that transduce receptor tyrosine kinase signaling through the extracellular signal regulated kinase (ERK). During embryogenesis, ERK acts as the primary signaling effector, driving fate acquisition and germ layer specification.

Hepatic cytochrome P450 function is reduced by life-long Western diet consumption in guinea pig independent of birth weight.

Introduction: Non-alcoholic fatty liver disease (NAFLD) is characterised by accumulation of triglycerides and cholesterol within the liver and dysregulation of specific hepatic cytochrome P450 (CYPs) activity. CYPs are involved in the metabolism of endogenous and exogenous chemicals. Hepatic CYP activity is dysregulated in human studies and animal models of a Western diet (WD) or low birth weight (LBW) independently, but the additive effects of LBW and postnatal WD consumption are unknown.

Brain Targeting and Toxicological Assessment of the Extracellular Vesicle-Packaged Antioxidant Catalase-SKL Following Intranasal Administration in Mice.

The antioxidant enzyme catalase represents an important therapeutic target due to its role in mitigating cellular reactive oxygen species that contribute to the pathogenesis of many disease states. Catalase-SKL (CAT-SKL), a genetically engineered, peroxisome-targeted, catalase derivative, was developed in order to increase the therapeutic potential of the enzyme, and has previously been shown to be effective in combating oxidative stress in a variety of in vitro and in vivo models, thereby mitigating cellular degeneration and death. In the present study we addressed important considerations for the development of an extracellular vesicle-packaged version of CAT-SKL (evCAT-SKL) as a therapeutic for neurodegenerative diseases by investigating its delivery potential to the brain when administered intranasally, and safety by assessing off-target toxicity in a mouse model.

Disrupting the DREAM transcriptional repressor complex induces apolipoprotein overexpression and systemic amyloidosis in mice.

DREAM (Dp, Rb-like, E2F, and MuvB) is a transcriptional repressor complex that regulates cell proliferation, and its loss causes neonatal lethality in mice. To investigate DREAM function in adult mice, we used an assembly-defective p107 protein and conditional deletion of its redundant family member p130. In the absence of DREAM assembly, mice displayed shortened survival characterized by systemic amyloidosis but no evidence of excessive cellular proliferation.

Vascularization of the human intervertebral disc: A scoping review.

Intervertebral discs (IVDs) are often referred to as the largest avascular structures of the human body, yet a collective resource characterizing the vascularization of the IVD does not exist. To address this gap, the objective of this study was to conduct a comprehensive search of the literature to review and summarize current knowledge of the prevalence and localization of blood supply in human IVDs, with a scoping review. A comprehensive search of peer-reviewed publications on the topic of IVD vascularization in humans was conducted across six electronic databases: PubMed, EMBASE, MEDLINE, Scopus, Web of Science, and BIOSIS Previews.

Dystrophic calcification and heterotopic ossification in fibrocartilaginous tissues of the spine in diffuse idiopathic skeletal hyperostosis (DISH).

Diffuse idiopathic skeletal hyperostosis (DISH) is a prevalent noninflammatory spondyloarthropathy characterized by ectopic mineral formation along the anterolateral aspect of the vertebral column, yet little is known about its underlying pathogenesis. Our objective was to evaluate the histopathological features and composition of ectopic mineral within spinal tissues affected by DISH in humans. Thoracic spine segments from six embalmed cadaveric donors (one female and five males; median age 82 years) meeting the radiographic diagnostic criteria for DISH were evaluated using radiological, histological, and physical analyses.

Stress-induced inactivation of the Staphylococcus aureus purine biosynthesis repressor leads to hypervirulence.

Staphylococcus aureus is a significant cause of human infection. Here, we demonstrate that mutations in the transcriptional repressor of purine biosynthesis, purR, enhance the pathogenic potential of S. aureus.

Section -Associated Calcium Oxalate Crystals in an Eurasian Eagle Owl ().

An adult male Eurasian eagle owl () housed at a wildlife rehabilitation facility in southern Oregon died after a short period of progressive ill-thrift. Radiographs taken prior to death demonstrated abnormal radiopaque material in the coelom and the owl was submitted for postmortem examination. Black pigmented fungus was noted grossly, particularly in the respiratory tissues, with abundant oxalate crystal deposition associated with and without hyphal elements subsequently observed histologically.

Histologic processing artifacts and inter-pathologist variation in measurement of inked margins of canine mast cell tumors.

Although quantitative assessment of margins is recommended for describing excision of cutaneous malignancies, there is poor understanding of limitations associated with this technique. We described and quantified histologic artifacts in inked margins and determined the association between artifacts and variance in histologic tumor-free margin (HTFM) measurements based on a novel grading scheme applied to 50 sections of normal canine skin and 56 radial margins taken from 15 different canine mast cell tumors (MCTs). Three broad categories of artifact were 1) tissue deformation at inked edges, 2) ink-associated artifacts, and 3) sectioning-associated artifacts.

Lymphoma Classification in Goats.

Lymphoma has been described in individual cases for goats but not systematically characterized in a larger cohort. This study aimed to subtype caprine lymphoma based on topographic and subgross distribution, immunophenotype, and cellular morphology following the World Health Organization classification system for hematopoietic tumors in domestic animals. Fifteen caprine lymphoma cases were assessed with 6 submitted as biopsy and 9 for postmortem examination.

Inactivation of Plasmodium spp. in plasma and platelet concentrates using riboflavin and ultraviolet light.

Background: Photochemical treatment of blood products could help prevent transfusion-transmitted malaria and reduce the need for donor deferrals. In this study we evaluated the effectiveness of riboflavin and ultraviolet (UV) light against both Plasmodium falciparum, which causes the most severe form of human malaria, and Plasmodium yoelii, an in vivo murine model for malaria.

Study Design And Methods: Plasma and platelet (PLT) concentrates were inoculated with either P.

Cystic fibrosis and normal human airway epithelial cell response to influenza a viral infection.

Viral infections produce severe respiratory morbidity in children with cystic fibrosis (CF). CF cells are more susceptible to virus in part because of impaired airway epithelial activation of signal transducer and activator of transcription 1 (Stat1). As Stat1 is a fundamental regulator of antiviral defenses, we hypothesized that there may be multiple alterations in the antiviral defense of CF epithelium compared with normal (NL).

Basic residues in the nucleocapsid domain of Gag are required for interaction of HIV-1 gag with ABCE1 (HP68), a cellular protein important for HIV-1 capsid assembly.

During human immunodeficiency virus, type 1 (HIV-1) assembly, Gag polypeptides multimerize into immature HIV-1 capsids. The cellular ATP-binding protein ABCE1 (also called HP68 or RNase L inhibitor) appears to be critical for proper assembly of the HIV-1 capsid. In primate cells, ABCE1 associates with Gag polypeptides present in immature capsid assembly intermediates.

Human epithelial beta-defensins 2 and 3 inhibit HIV-1 replication.

Objective: Mechanisms underlying mucosal transmission of HIV-1 are incompletely understood. We describe the anti-HIV-1 activity of human beta-defensins (hBD), small cationic molecules that provide protection at mucosal surfaces.

Methods And Results: HIV-1 induced expression of hBD-2 and -3 mRNA (but not that of hBD-1) 4- to 78-fold, respectively, above baseline in normal human oral epithelial cells.

Role of the human immunodeficiency virus type 1 envelope gene in viral fitness.

A human host offers a variety of microenvironments to the infecting human immunodeficiency virus type 1 (HIV-1), resulting in various selective pressures, most of them directed against the envelope (env) gene. Therefore, it seems evident that the replicative capacity of the virus is largely related to viral entry. In this study we have used growth competition experiments and TaqMan real-time PCR detection to measure the fitness of subtype B HIV-1 primary isolates and autologous env-recombinant viruses in order to analyze the contribution of wild-type env sequences to overall HIV-1 fitness.

Leishmania major chromosome 3 contains two long convergent polycistronic gene clusters separated by a tRNA gene.

Leishmania parasites (order Kinetoplastida, family Trypanosomatidae) cause a spectrum of human diseases ranging from asymptomatic to lethal. The approximately 33.6 Mb genome is distributed among 36 chromosome pairs that range in size from approximately 0.

Identification of a host protein essential for assembly of immature HIV-1 capsids.

To form an immature HIV-1 capsid, 1,500 HIV-1 Gag (p55) polypeptides must assemble properly along the host cell plasma membrane. Insect cells and many higher eukaryotic cell types support efficient capsid assembly, but yeast and murine cells do not, indicating that host machinery is required for immature HIV-1 capsid formation. Additionally, in a cell-free system that reconstitutes HIV-1 capsid formation, post-translational assembly events require ATP and a subcellular fraction, suggesting a requirement for a cellular ATP-binding protein.