Clustered Archimax Copulas

When modeling multivariate phenomena, properly capturing the joint extremal behavior is often one of the many concerns. Archimax copulas appear as successful candidates in case of asymptotic dependence. In this paper, the class of Archimax copulas is extended via their stochastic representation to a clustered construction. These clustered Archimax copulas are characterized by a partition of the random variables into groups linked by a radial copula; each cluster is Archimax and therefore defined by its own Archimedean generator and stable tail dependence function. The proposed extension allows for both asymptotic dependence and independence between the clusters, a property which is sought, for example, in applications in environmental sciences and finance. The model also inherits from the ability of Archimax copulas to capture dependence between variables at pre-extreme levels. The asymptotic behavior of the model is established, leading to a rich class of stable tail dependence functions.Comment: 42 pages, 10 figure

Aven recognition of RNA G-quadruplexes regulates translation of the mixed lineage leukemia protooncogenes

Abstract: G-quadruplexes (G4) are extremely stable secondary structures forming stacks of guanine tetrads. DNA G4 structures have been extensively studied, however, less is known about G4 motifs in mRNAs, especially in their coding sequences. Herein, we show that Aven stimulates the mRNA translation of the mixed lineage leukemia (MLL) proto-oncogene in an arginine methylation-dependent manner. The Aven RGG/RG motif bound G4 structures within the coding regions of the MLL1 and MLL4 mRNAs increasing their polysomal association and translation, resulting in the induction of transcription of leukemic genes. The DHX36 RNA helicase associated with the Aven complex and was required for optimal translation of G4 mRNAs. Depletion of Aven led to a decrease in synthesis of MLL1 and MLL4 proteins resulting in reduced proliferation of leukemic cells. These findings identify an Aven-centered complex that stimulates the translation of G4 harboring mRNAs, thereby promoting survival of leukemic cells

3′ UTR G-quadruplexes regulate miRNA binding

Abstract : MicroRNAs (miRNAs) are small noncoding RNAs that repress the translation of their target genes. It has previously been shown that a target’s availability to miRNA can be affected by its structure. G-quadruplexes (G4) are noncanonical structures adopted by G-rich nucleic acids that have been shown to have multiple biological functions. In this study, whether or not G4 structures’ presence in the 3′ UTRs of mRNAs can hinder miRNA binding was investigated. Putative G4 overlapping with predicted miRNAs’ binding sites was searched for, and 44,294 hits were found in humans. The FADS2 mRNA/mir331-3p pair was selected as a model example. In-line probing and G4-specific fluorescent ligand experiments binding were performed and confirmed the presence of a G4 near the predicted miRNA binding site. Subsequent luciferase assays showed that the presence of the G4 prevents the binding of mir331-3p in cellulo. Together, these results served as proof of concept that a G4 structure present in a 3′ UTR sequence should be taken into consideration when predicting miRNA binding sites

Pharmacogenomics of the efficacy and safety of Colchicine in COLCOT

© 2021 The Authors. Circulation: Genomic and Precision Medicine is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited and is not used for commercial purposes.Background: The randomized, placebo-controlled COLCOT (Colchicine Cardiovascular Outcomes Trial) has shown the benefits of colchicine 0.5 mg daily to lower the rate of ischemic cardiovascular events in patients with a recent myocardial infarction. Here, we conducted a post hoc pharmacogenomic study of COLCOT with the aim to identify genetic predictors of the efficacy and safety of treatment with colchicine. Methods: There were 1522 participants of European ancestry from the COLCOT trial available for the pharmacogenomic study of COLCOT trial. The pharmacogenomic study's primary cardiovascular end point was defined as for the main trial, as time to first occurrence of cardiovascular death, resuscitated cardiac arrest, myocardial infarction, stroke, or urgent hospitalization for angina requiring coronary revascularization. The safety end point was time to the first report of gastrointestinal events. Patients' DNA was genotyped using the Illumina Global Screening array followed by imputation. We performed a genome-wide association study in colchicine-treated patients. Results: None of the genetic variants passed the genome-wide association study significance threshold for the primary cardiovascular end point conducted in 702 patients in the colchicine arm who were compliant to medication. The genome-wide association study for gastrointestinal events was conducted in all 767 patients in the colchicine arm and found 2 significant association signals, one with lead variant rs6916345 (hazard ratio, 1.89 [95% CI, 1.52-2.35], P=7.41×10-9) in a locus which colocalizes with Crohn disease, and one with lead variant rs74795203 (hazard ratio, 2.51 [95% CI, 1.82-3.47]; P=2.70×10-8), an intronic variant in gene SEPHS1. The interaction terms between the genetic variants and treatment with colchicine versus placebo were significant. Conclusions: We found 2 genomic regions associated with gastrointestinal events in patients treated with colchicine. Those findings will benefit from replication to confirm that some patients may have genetic predispositions to lower tolerability of treatment with colchicine.info:eu-repo/semantics/publishedVersio

SARS-CoV-2 spike antigen-specific B cell and antibody responses in pre-vaccination period COVID-19 convalescent males and females with or without post-covid condition

Background Following SARS-CoV-2 infection a significant proportion of convalescent individuals develop the post-COVID condition (PCC) that is characterized by wide spectrum of symptoms encompassing various organs. Even though the underlying pathophysiology of PCC is not known, detection of viral transcripts and antigens in tissues other than lungs raise the possibility that PCC may be a consequence of aberrant immune response to the viral antigens. To test this hypothesis, we evaluated B cell and antibody responses to the SARS-CoV-2 antigens in PCC patients who experienced mild COVID-19 disease during the pre-vaccination period of COVID-19 pandemic. Methods The study subjects included unvaccinated male and female subjects who developed PCC or not (No-PCC) after clearing RT-PCR confirmed mild COVID-19 infection. SARS-CoV-2 D614G and omicron RBD specific B cell subsets in peripheral circulation were assessed by flow cytometry. IgG, IgG3 and IgA antibody titers toward RBD, spike and nucleocapsid antigens in the plasma were evaluated by ELISA. Results The frequency of the B cells specific to D614G-RBD were comparable in convalescent groups with and without PCC in both males and females. Notably, in females with PCC, the anti-D614G RBD specific double negative (IgD-CD27-) B cells showed significant correlation with the number of symptoms at acute of infection. Anti-spike antibody responses were also higher at 3 months post-infection in females who developed PCC, but not in the male PCC group. On the other hand, the male PCC group also showed consistently high anti-RBD IgG responses compared to all other groups. Conclusions The antibody responses to the spike protein, but not the anti-RBD B cell responses diverge between convalescent males and females who develop PCC. Our findings also suggest that sex-related factors may also be involved in the development of PCC via modulating antibody responses to the SARS-CoV-2 antigens

Metabolite Profiles of Incident Diabetes and Heterogeneity of Treatment Effect in the Diabetes Prevention Program

Novel biomarkers of type 2 diabetes (T2D) and response to preventative treatment in individuals with similar clinical risk may highlight metabolic pathways that are important in disease development. We profiled 331 metabolites in 2,015 baseline plasma samples from the Diabetes Prevention Program (DPP). Cox models were used to determine associations between metabolites and incident T2D, as well as whether associations differed by treatment group (i.e., lifestyle [ILS], metformin [MET], or placebo [PLA]), over an average of 3.2 years of follow-up. We found 69 metabolites associated with incident T2D regardless of treatment randomization. In particular, cytosine was novel and associated with the lowest risk. In an exploratory analysis, 35 baseline metabolite associations with incident T2D differed across the treatment groups. Stratification by baseline levels of several of these metabolites, including specific phospholipids and AMP, modified the effect that ILS or MET had on diabetes development. Our findings highlight novel markers of diabetes risk and preventative treatment effect in individuals who are clinically at high risk and motivate further studies to validate these interactions