LINE1 and PRC2 control nucleolar organization and repression of the 8C state in human ESCs.

The mechanisms that ensure developmental progression in the early human embryo remain largely unknown. Here, we show that the family of long interspersed nuclear element 1 (LINE1) transposons prevents the reversion of naive human embryonic stem cells (hESCs) to 8-cell-like cells (8CLCs). LINE1 RNA contributes to maintenance of H3K27me3 levels, particularly at chromosome 19 (Chr19).

Autonomous transposons tune their sequences to ensure somatic suppression.

Transposable elements (TEs) are a major constituent of human genes, occupying approximately half of the intronic space. During pre-messenger RNA synthesis, intronic TEs are transcribed along with their host genes but rarely contribute to the final mRNA product because they are spliced out together with the intron and rapidly degraded. Paradoxically, TEs are an abundant source of RNA-processing signals through which they can create new introns, and also functional or non-functional chimeric transcripts.

Lessons learned from the use of COVID-19 convalescent plasma at Kaiser Permanente.

Background: In April 2020, the Mayo Clinic helped establish the US Food and Drug Administration Expanded Access Protocol for COVID-19 (coronavirus disease 2019) convalescent plasma (CCP). The effectiveness of CCP in the published literature is contradictory because some retrospective studies showed benefit in reducing mortality and severe illness, whereas prospective randomized controlled trials demonstrated no benefit of CCP.

Objectives: To discuss (1) the implementation of CCP across Kaiser Permanente Southern California between April 2020 and April 2021, (2) retrospective multivariable analysis of 2,831 patients with COVID-19 who were transfused with CCP compared with 18,475 patients with COVID-19 who did not receive CCP, (3) how to reconcile contradictory published data regarding the efficacy of CCP, and (4) guidance regarding the future use of convalescent plasma in a large community hospital setting.

Regulatory CD4 T Cells Recognize Major Histocompatibility Complex Class II Molecule-Restricted Peptide Epitopes of Apolipoprotein B.

Background: CD4 T cells play an important role in atherosclerosis, but their antigen specificity is poorly understood. Immunization with apolipoprotein B (ApoB, core protein of low density lipoprotein) is known to be atheroprotective in animal models. Here, we report on a human APOB peptide, p18, that is sequence-identical in mouse ApoB and binds to both mouse and human major histocompatibility complex class II molecules.

The Utility of the Reflux Symptom Index for Diagnosis of Laryngopharyngeal Reflux in an Allergy Patient Population.

Background: Laryngopharyngeal reflux (LPR) is associated with asthma, vocal cord dysfunction, cough, postnasal drainage, and throat irritation. The Reflux Symptom Index (RSI) is a clinical tool to predict the presence of LPR, but a threshold RSI score has never been validated for the diagnosis of LPR in an allergic patient population.

Objective: To identify the optimal threshold RSI score predictive of LPR in an allergy clinic population.

Anabolic androgen use in the management of hereditary angioedema: Not so cheap after all.

Background: Hereditary angioedema due to C1 inhibitor deficiency (HAE) is a rare, life-threatening disease that imposes a significant burden on affected patients. 17α-alkylated androgens (anabolic androgens) decrease attack frequency and severity but carry the risk of potentially serious dose-related adverse effects. Despite the emergence of targeted therapies for HAE, continued anabolic androgen use has been driven in part by their low cost.

T-Cells Specific for a Self-Peptide of ApoB-100 Exacerbate Aortic Atheroma in Murine Atherosclerosis.

On the basis of mouse I-A-binding motifs, two sequences of the murine apolipoprotein B-100 (mApoB-100), mApoB-100 (designated P3) and mApoB-100 (designated P6), were found to be immunogenic. In this report, we show that P6 is also atherogenic. Immunization of mice fed a high-fat diet (HFD) with P6 resulted in enhanced development of aortic atheroma as compared to control mice immunized with an irrelevant peptide MOG or with complete Freund's adjuvant alone.

Atheroprotective vaccination with MHC-II-restricted ApoB peptides induces peritoneal IL-10-producing CD4 T cells.

Although immunization with major histocompatibility complex (MHC) class II-restricted apolipoprotein B (ApoB) peptides has been shown to be atheroprotective, the mechanism is unclear. Here, we investigated CD4 T cell populations in immunized atherosclerotic mice. Peptides (16-mers) from mouse ApoB, the core protein of low-density lipoprotein (LDL), were screened for binding to I-A by computer prediction and confirmed by radiolabeled peptide competition.

Effect of catastrophic wildfires on asthmatic outcomes in obese children: breathing fire.

Background: Air pollutants from wildfires and obesity independently exacerbate asthma, yet no study has determined the combined effects of these 2 variables on asthma outcomes.

Objective: To determine the effect of 2 catastrophic wildfires affecting the Southern California region (in 2003 and 2007) on several asthma outcomes in a cohort of children.

Methods: To investigate the association between wildfire exposure and asthma outcomes, we stratified our study population by body mass index categories (underweight, normal, overweight, and obese) and zip codes (to distinguish individuals who were closer to the fires vs farther away).

Vaccination to modulate atherosclerosis.

Atherosclerosis is a chronic inflammatory disease of the artery wall. Adaptive immunity plays a key role in the pathogenesis of atherosclerosis. Recently, modulation of the immune response against atherosclerotic plaque antigen(s) has attracted attention as a potentially preventive and therapeutic approach.

Atheroprotective Vaccination with MHC-II Restricted Peptides from ApoB-100.

Background: Subsets of CD4(+) T-cells have been proposed to serve differential roles in the development of atherosclerosis. Some T-cell types are atherogenic (T-helper type 1), while others are thought to be protective (regulatory T-cells). Lineage commitment toward one type of helper T-cell versus another is strongly influenced by the inflammatory context in which antigens are recognized.

T cells in atherosclerosis.

Atherosclerosis is a chronic inflammatory disease of the artery wall. Atherosclerotic lesions contain monocytes, macrophages, smooth muscle cells and T lymphocytes. Here, we review the role of T-lymphocyte subsets in atherosclerosis.

Recognizing and managing hereditary angioedema.

Hereditary angioedema is a rare but life-threatening disease characterized by recurring attacks of swelling of any part of the body, without hives. Prompt recognition is critical so that treatment can be started to minimize morbidity and the risk of death. Drugs have recently become available to prevent and treat acute attacks.

Light-sheet Bayesian microscopy enables deep-cell super-resolution imaging of heterochromatin in live human embryonic stem cells.

Background: Heterochromatin in the nucleus of human embryonic cells plays an important role in the epigenetic regulation of gene expression. The architecture of heterochromatin and its dynamic organization remain elusive because of the lack of fast and high-resolution deep-cell imaging tools. We enable this task by advancing instrumental and algorithmic implementation of the localization-based super-resolution technique.

Bilateral nephrectomy for the treatment of refractory lupus nephritis with features overlapping with thrombotic microangiopathy resembling thrombotic thrombocytopenia purpura.

We report a patient with a diagnosis of systemic lupus erythematosus who concurrently developed a syndrome of thrombotic microangiopathy that resembled thrombotic thrombocytopenic purpura. The patient underwent plasma exchange and immunosuppressive therapy for months before clinical improvement was finally achieved through bilateral nephrectomy. Ultimately, our patient died of disseminated aspergillosis from prolonged immunosuppression.

House dust bioactivities predict skin prick test reactivity for children with high risk of allergy.

Background: Although evidence suggests that ambient exposures to endotoxin and other immunostimulants during early life influence allergic risk, efforts to understand this host-environment relationship have been hampered by a paucity of relevant assays.

Objectives: These investigations determined whether parameters of house dust extract (HDE) bioactivity were predictive of allergen skin prick test (SPT) reactivity for infants at high risk of allergy participating in the Cincinnati Childhood Allergy and Air Pollution Study (CCAAPS).

Methods: We conducted a nested case-control study, selecting 99 CCAAPS children who had positive SPT results to at least 1 aeroallergen at age 3 years and 101 subjects with negative SPT results.

Allergen tolerance versus the allergic march: the hygiene hypothesis revisited.

In addition to genetics, several environmental variables appear to impact allergic risk. Meta-analyses of epidemiologic studies presented in this article demonstrate a correlation between specific ambient exposures (eg, livestock, pets, endotoxin, and unpasteurized milk ingestion) and reduced allergic risk during childhood. Additional laboratory investigations discussed in this review characterized the intrinsic immunostimulatory activities of living environments.

Update on toll-like receptor-directed therapies for human disease.

Innate responses to microbes are mediated in large part by toll-like receptors (TLRs), which recognise a diverse range of molecules produced by viruses, bacteria and fungi. Great effort has been directed towards translating this knowledge into the development of new therapies for a wide spectrum of diseases, including infectious, malignant, autoimmune and allergic diseases. This review will provide a brief update on completed, ongoing and planned clinical trials of TLR ligand-based therapies for the treatment of diseases in humans.

Defining a role for ambient TLR ligand exposures in the genesis and prevention of allergic diseases.

Environmental variables responsible for the increasing allergic disease burden observed in developed countries over the last century have yet to be adequately characterized. Meta-analyses of epidemiological studies presented in the first half of this paper demonstrate a correlation between farm-associated exposures (i.e.