Prevalence of anti-myelin oligodendrocyte glycoprotein antibodies across neuroinflammatory and neurodegenerative diseases.

Inflammatory central nervous system (CNS) diseases, such as multiple sclerosis (MS) and myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD), are characterized by humoral immune abnormalities. Anti-MOG antibodies are not specific to MOGAD, with their presence described in MS. Autoantibodies may also be present and play a role in various neurodegenerative diseases.

DDIT4L regulates mitochondrial and innate immune activities in early life.

Pattern recognition receptor responses are profoundly attenuated before the third trimester of gestation in the relatively low-oxygen human fetal environment. However, the mechanisms regulating these responses are uncharacterized. Herein, genome-wide transcription and functional metabolic experiments in primary neonatal monocytes linked the negative mTOR regulator DDIT4L to metabolic stress, cellular bioenergetics, and innate immune activity.

Transient Receptor Potential Vanilloid 4-Dependent Microglial Function in Myelin Injury and Repair.

Microglia are found pathologically at all stages of multiple sclerosis (MS) lesion development and are hypothesized to contribute to both inflammatory injury and neuroprotection in the MS brain. Transient receptor potential vanilloid 4 (TRPV4) channels are widely expressed, play an important role as environmental sensors, and are involved in calcium homeostasis for a variety of cells. TRPV4 modulates myeloid cell phagocytosis in the periphery and microglial motility in the central nervous system.

Antigen-specific depletion of CD4 T cells by CAR T cells reveals distinct roles of higher- and lower-affinity TCRs during autoimmunity.

Both higher- and lower-affinity self-reactive CD4 T cells are expanded in autoimmunity; however, their individual contribution to disease remains unclear. We addressed this question using peptide-MHCII chimeric antigen receptor (pMHCII-CAR) T cells to specifically deplete peptide-reactive T cells in mice. Integration of improvements in CAR engineering with TCR repertoire analysis was critical for interrogating in vivo the role of TCR affinity in autoimmunity.

Biosynthesis and metabolism of endocannabinoids and their congeners from the monoacylglycerol and N-acyl-ethanolamine families.

The endocannabinoids 2-arachidonoyl-glycerol (2-AG) and N-arachidonoyl-ethanolamine (AEA) are eicosanoids implicated in numerous physiological processes like appetite, adipogenesis, inflammatory pain and inflammation. They mediate most of their physiological effects by activating the cannabinoid (CB) receptors 1 and 2. Other than directly binding to the CB receptors, 2-AG and AEA are also metabolized by most eicosanoid biosynthetic enzymes, yielding many metabolites that are part of the oxyendocannabinoidome.

A promising mouse model for Friedreich Ataxia progressing like human patients.

Friedreich Ataxia (FRDA) is a genetic disease caused by an expended GAA repeat in the FXN gene leading to a reduction in frataxin protein production. Frataxin is an essential protein involved in mitochondrial iron-sulfur-cluster formation, its absence affecting numerous cellular rections. In patients, the disease leads to a progressive neuromuscular degeneration and, most of the time, death from heart failure.

Cytokines and Lipid Mediators of Inflammation in Lungs of SARS-CoV-2 Infected Mice.

Coronavirus disease 19 (COVID-19) is the clinical manifestation of severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) infection. A hallmark of COVID-19 is a lung inflammation characterized by an abundant leukocyte infiltrate, elevated levels of cytokines/chemokines, lipid mediators of inflammation (LMI) and microthrombotic events. Animal models are useful for understanding the pathophysiological events leading to COVID-19.

The plastome of Arctic (Fabaceae) is significantly different from that of and other related species.

Anatomical and physiological specializations for plant adaptation to harsh climates result from molecular mechanisms that can be encoded in the nucleus or organelle. In this study, the complete plastomes of an arctic species, Bunge (Fabaceae), and a closely related temperate species, Douglas ex Hook., were assembled, annotated, and analyzed to identify differences that might help explain their adaptation to different environments.

Risk Stratification for Early-Onset Colorectal Cancer Using a Combination of Genetic and Environmental Risk Scores: An International Multi-Center Study.

Background: The incidence of colorectal cancer (CRC) among individuals aged younger than 50 years has been increasing. As screening guidelines lower the recommended age of screening initiation, concerns including the burden on screening capacity and costs have been recognized, suggesting that an individualized approach may be warranted. We developed risk prediction models for early-onset CRC that incorporate an environmental risk score (ERS), including 16 lifestyle and environmental factors, and a polygenic risk score (PRS) of 141 variants.

Human and Mouse Eosinophils Differ in Their Ability to Biosynthesize Eicosanoids, Docosanoids, the Endocannabinoid 2-Arachidonoyl-glycerol and Its Congeners.

High eosinophil (EOS) counts are a key feature of eosinophilic asthma. EOS notably affect asthmatic response by generating several lipid mediators. Mice have been utilized in hopes of defining new pharmacological targets to treat asthma.

Biosynthesis of the Novel Endogenous 15-Lipoxygenase Metabolites -13-Hydroxy-octodecadienoyl-ethanolamine and 13-Hydroxy-octodecadienoyl-glycerol by Human Neutrophils and Eosinophils.

The endocannabinoids 2-arachidonoyl-glycerol and -arachidonoyl-ethanolamine are lipids regulating many physiological processes, notably inflammation. Endocannabinoid hydrolysis inhibitors are now being investigated as potential anti-inflammatory agents. In addition to 2-arachidonoyl-glycerol and -arachidonoyl-ethanolamine, the endocannabinoidome also includes other monoacylglycerols and -acyl-ethanolamines such as 1-linoleoyl-glycerol (1-LG) and -linoleoyl-ethanolamine (LEA).

Chemokines and eicosanoids fuel the hyperinflammation within the lungs of patients with severe COVID-19.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can lead to a variety of clinical outcomes, ranging from the absence of symptoms to severe acute respiratory disease and ultimately death. A feature of patients with severe coronavirus disease 2019 (COVID-19) is the abundance of inflammatory cytokines in the blood. Elevated levels of cytokines are predictive of infection severity and clinical outcome.

Nongenetic Determinants of Risk for Early-Onset Colorectal Cancer.

Background: Incidence of early-onset (younger than 50 years of age) colorectal cancer (CRC) is increasing in many countries. Thus, elucidating the role of traditional CRC risk factors in early-onset CRC is a high priority. We sought to determine whether risk factors associated with late-onset CRC were also linked to early-onset CRC and whether association patterns differed by anatomic subsite.

High levels of eicosanoids and docosanoids in the lungs of intubated COVID-19 patients.

Severe acute respiratory syndrome coronavirus 2 is responsible for coronavirus disease 2019 (COVID-19). While COVID-19 is often benign, a subset of patients develops severe multilobar pneumonia that can progress to an acute respiratory distress syndrome. There is no cure for severe COVID-19 and few treatments significantly improved clinical outcome.

Synthesis and molecular targets of N-13-hydroxy-octadienoyl-ethanolamine, a novel endogenous bioactive 15-lipoxygenase-derived metabolite of N-linoleoyl-ethanolamine found in the skin and saliva.

N-Arachidonoyl-ethanolamine (AEA) is an endocannabinoid (eCB) and endogenous lipid mimicking many of the effects of Δ-tetrahydrocannabinol, notably on brain functions, appetite, pain and inflammation. The eCBs and eCB-like compounds contain fatty acids, the main classes being the monoacylglycerols and the N-acyl-ethanolamines (NAEs). Thus, each long chain fatty acid likely exists under the form of a monoacylglycerol and NAE, as it is the case for arachidonic acid (AA) and linoleic acid (LA).

Critical Casimir interactions of colloids in micellar critical solutions.

We study the temperature-dependence of critical Casimir interactions in a critical micellar solution of the nonionic surfactant C12E5 dissolved in water. Experimentally, this is achieved with total internal reflection microscopy (TIRM) which measures the interaction between a single particle and a flat wall. For comparison, we also studied the pair interactions of a two dimensional layer of colloidal particles in the identical micellar system which yields good agreement with the TIRM results.

Polypharmacy in Older Adults Hospitalized for Heart Failure.

Background: Despite potential harm that can result from polypharmacy, real-world data on polypharmacy in the setting of heart failure (HF) are limited. We sought to address this knowledge gap by studying older adults hospitalized for HF derived from the REGARDS study (Reasons for Geographic and Racial Differences in Stroke).

Methods: We examined 558 older adults aged ≥65 years with adjudicated HF hospitalizations from 380 hospitals across the United States.

Development and characterization of 14 microsatellites for the eastern chipmunk, Tamias striatus.

The number of microsatellite markers currently available for the eastern chipmunk Tamias striatus provides limited capacity to achieve sufficient pedigree building for the study of their genetic structure and relatedness patterns. We developed microsatellite loci for the eastern chipmunk, a small rodent commonly found in eastern North America. More specifically, we report data for 14 loci and 50 individuals genotyped from a population in southern Québec, Canada.

Endocannabinoid hydrolysis inhibition unmasks that unsaturated fatty acids induce a robust biosynthesis of 2-arachidonoyl-glycerol and its congeners in human myeloid leukocytes.

The endocannabinoid (eCB) 2-arachidonoyl-gycerol (2-AG) modulates immune responses by activating cannabinoid receptors or through its multiple metabolites, notably eicosanoids. Thus, 2-AG hydrolysis inhibition might represent an interesting anti-inflammatory strategy that would simultaneously increase the levels of 2-AG and decrease those of eicosanoids. Accordingly, 2-AG hydrolysis inhibition increased 2-AG half-life in neutrophils.

Cumulative Burden of Colorectal Cancer-Associated Genetic Variants Is More Strongly Associated With Early-Onset vs Late-Onset Cancer.

Background & Aims: Early-onset colorectal cancer (CRC, in persons younger than 50 years old) is increasing in incidence; yet, in the absence of a family history of CRC, this population lacks harmonized recommendations for prevention. We aimed to determine whether a polygenic risk score (PRS) developed from 95 CRC-associated common genetic risk variants was associated with risk for early-onset CRC.

Methods: We studied risk for CRC associated with a weighted PRS in 12,197 participants younger than 50 years old vs 95,865 participants 50 years or older.

Prescribing Patterns of Heart Failure-Exacerbating Medications Following a Heart Failure Hospitalization.

Objectives: This study sought to describe the patterns of heart failure (HF)-exacerbating medications used among older adults hospitalized for HF and to examine determinants of HF-exacerbating medication use.

Background: HF-exacerbating medications can potentially contribute to adverse outcomes and could represent an important target for future strategies to improve post-hospitalization outcomes.

Methods: Medicare beneficiaries ≥65 years of age with an adjudicated HF hospitalization between 2003 and 2014 were derived from the geographically diverse REGARDS (Reasons for Geographic and Racial Difference in Stroke) cohort study.

Neutrophils promote VLA-4-dependent B cell antigen presentation and accumulation within the meninges during neuroinflammation.

The success of B cell depletion therapies and identification of leptomeningeal ectopic lymphoid tissue (ELT) in patients with multiple sclerosis (MS) has renewed interest in the antibody-independent pathogenic functions of B cells during neuroinflammation. The timing and location of B cell antigen presentation during MS and its animal model experimental autoimmune encephalomyelitis (EAE) remain undefined. Using a new EAE system that incorporates temporal regulation of MHCII expression by myelin-specific B cells, we observed the rapid formation of large B cell clusters in the spinal cord subarachnoid space.

Human leukocytes differentially express endocannabinoid-glycerol lipases and hydrolyze 2-arachidonoyl-glycerol and its metabolites from the 15-lipoxygenase and cyclooxygenase pathways.

2-Arachidonoyl-glycerol (2-AG) is an endocannabinoid with anti-inflammatory properties. Blocking 2-AG hydrolysis to enhance CB signaling has proven effective in mouse models of inflammation. However, the expression of 2-AG lipases has never been thoroughly investigated in human leukocytes.