Type 1 diabetes (T1D) is characterized by the destruction of pancreatic β-cells. Several observations have renewed the interest in β-cell RNA sensors and editors. Here, we report that -methyladenosine (mA) is an adaptive β-cell safeguard mechanism that controls the amplitude and duration of the antiviral innate immune response at T1D onset.
View Article and Find Full Text PDFTriggering lysosome-regulated immunogenic cell death (ICD, e.g., pyroptosis and necroptosis) with nanomedicines is an emerging approach for turning an "immune-cold" tumor "hot"-a key challenge faced by cancer immunotherapies.
View Article and Find Full Text PDFThe lack of physiologically relevant models has hampered progress in understanding human lung development and disease. Here, we describe a protocol in which human induced pluripotent stem cells (hiPSCs) undergo stepwise differentiation into definitive endoderm (>88% population) to three-dimensional (3D) lung organoids (LORGs), which contain both epithelial and mesenchymal cellular architecture and display proximal and distal airway patterning. These LORGs can maintained for more than 90 days by re-embedding in the Matrigel.
View Article and Find Full Text PDFN -methyladenosine (m A), the most abundant internal modification in eukaryotic mRNA, plays important roles in many physiological and pathological processes, including the development and progression of cancer. RNA modification by m A is regulated by methyltransferases, demethylases, and m A-binding proteins that function in large part by regulating mRNA expression and function. Here, we investigate the expression of m A regulatory proteins in breast cancer.
View Article and Find Full Text PDFThe factors contributing to the rapid emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) BA.4 and BA.5 subvariants in populations that experienced recent surges of BA.
View Article and Find Full Text PDFExcessive erythrocytosis (EE) is a major hallmark of patients suffering from chronic mountain sickness (CMS, also known as Monge's disease) and is responsible for major morbidity and even mortality in early adulthood. We took advantage of unique populations, one living at high altitude (Peru) showing EE, with another population, at the same altitude and region, showing no evidence of EE (non-CMS). Through RNA-Seq, we identified and validated the function of a group of long noncoding RNAs (lncRNAs) that regulate erythropoiesis in Monge's disease, but not in the non-CMS population.
View Article and Find Full Text PDFUnlabelled: Although immune checkpoint inhibitors targeting T-cell immunoregulatory proteins have revolutionized cancer treatment, they are effective only in a limited number of patients, and new strategies are needed to enhance tumor responses to immunotherapies. Deletion of protein tyrosine phosphatase non-receptor type 2 (Ptpn2), a regulator of growth factor and cytokine signaling pathways, has been shown to sensitize murine B16F10 melanoma cells to IFNγ and anti-PD-1 immunotherapy. Here, we investigated the potential therapeutic utility of small-molecule PTPN2 inhibitors.
View Article and Find Full Text PDFType 1 Diabetes (T1D) is characterized by autoimmune-mediated destruction of insulin-producing β-cells. Several observations have renewed interest in the innate immune system as an initiator of the disease process against β-cells. Here, we show that N -Methyladenosine (m A) is an adaptive β-cell safeguard mechanism that accelerates mRNA decay of the 2'-5'-oligoadenylate synthetase (OAS) genes to control the antiviral innate immune response at T1D onset.
View Article and Find Full Text PDFInfection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to be a major health problem worldwide. Due to the fast emergence of SARS-CoV-2 variants, understanding the molecular mechanisms of viral pathogenesis and developing novel inhibitors are essential and urgent. Here, we investigated the potential roles of ,2'--dimethyladenosine (mA), one of the most abundant modifications of eukaryotic messenger ribonucleic acid (mRNAs), in SARS-CoV-2 infection of human cells.
View Article and Find Full Text PDFWe isolated a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) BA.2 variant from a person with coronavirus disease 2019 recrudescence after nirmatrelvir/ritonavir treatment. Antiviral sensitivity and neutralizing antibody testing were performed with both parental SARS-CoV-2 and multiple variants of concern.
View Article and Find Full Text PDFThe retrovirus human immunodeficiency virus-1 (HIV-1) is the causative agent of AIDS. Although treatment of HIV/AIDS with antiretroviral therapy provides suppression of viremia, latent reservoirs of integrated proviruses preclude cure by current antiviral treatments. Understanding the mechanisms of host-viral interactions may elucidate new treatment strategies.
View Article and Find Full Text PDFTo address the need for multivalent vaccines against that can be rapidly developed and manufactured, we compared antibody responses against SARS-CoV, SARS-CoV-2, and several variants of concern in mice immunized with mRNA-lipid nanoparticle vaccines encoding homodimers or heterodimers of SARS-CoV/SARS-CoV-2 receptor-binding domains. All vaccine constructs induced robust anti-viral antibody responses, and the heterodimeric vaccine elicited an IgG response capable of cross-neutralizing SARS-CoV, SARS-CoV-2 Wuhan-Hu-1, B.1.
View Article and Find Full Text PDFWiley Interdiscip Rev RNA
November 2022
More than 100 chemical modifications of RNA, termed the epitranscriptome, have been described, most of which occur in prokaryotic and eukaryotic ribosomal, transfer, and noncoding RNA and eukaryotic messenger RNA. DNA and RNA viruses can modify their RNA either directly via genome-encoded enzymes or by hijacking the host enzymatic machinery. Among the many RNA modifications described to date, four play particularly important roles in promoting viral infection by facilitating viral gene expression and replication and by enabling escape from the host innate immune response.
View Article and Find Full Text PDF-methylation of adenosine (m6A) is the most abundant internal mRNA modification and is an important post-transcriptional regulator of gene expression. Here, we describe a protocol for methylated RNA immunoprecipitation sequencing (MeRIP-Seq) to detect and quantify m6A modifications in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA. The protocol is optimized for low viral RNA levels and is readily adaptable for other applications.
View Article and Find Full Text PDFThe emergence of a new coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), presents an urgent public health crisis. Without available targeted therapies, treatment options remain limited for COVID-19 patients. Using medicinal chemistry and rational drug design strategies, we identify a 2-phenyl-1,2-benzoselenazol-3-one class of compounds targeting the SARS-CoV-2 main protease (M).
View Article and Find Full Text PDFN,2'-O-dimethyladenosine (mAm) is an abundant RNA modification located adjacent to the 5'-end of the mRNA 7-methylguanosine (mG) cap structure. mA methylation on 2'-O-methylated A at the 5'-ends of mRNAs is catalyzed by the methyltransferase Phosphorylated CTD Interacting Factor 1 (PCIF1). The role of mAm and the function of PCIF1 in regulating host-pathogens interactions are unknown.
View Article and Find Full Text PDFIt is urgent and important to understand the relationship of the widespread severe acute respiratory syndrome coronavirus clade 2 (SARS-CoV-2) with host immune response and study the underlining molecular mechanism. N-methylation of adenosine (m6A) in RNA regulates many physiological and disease processes. Here, we investigate m6A modification of the SARS-CoV-2 gene in regulating the host cell innate immune response.
View Article and Find Full Text PDFCOVID-19 is a transmissible respiratory disease caused by a novel coronavirus, SARS-CoV-2, and has become a global health emergency. There is an urgent need for robust and practical in vitro model systems to investigate viral pathogenesis. Here, we generated human induced pluripotent stem cell (iPSC)-derived lung organoids (LORGs), cerebral organoids (CORGs), neural progenitor cells (NPCs), neurons, and astrocytes.
View Article and Find Full Text PDFGlioblastoma multiforme (GBM) is the most lethal primary brain tumor characterized by high cellular and molecular heterogeneity, hypervascularization, and innate drug resistance. Cellular components and extracellular matrix (ECM) are the two primary sources of heterogeneity in GBM. Here, biomimetic tri-regional GBM models with tumor regions, acellular ECM regions, and an endothelial region with regional stiffnesses patterned corresponding to the GBM stroma, pathological or normal brain parenchyma, and brain capillaries, are developed.
View Article and Find Full Text PDF-methyladenosine (mA) has emerged as the most abundant mRNA modification that regulates gene expression in many physiological processes. mA modification in RNA controls cellular proliferation and pluripotency and has been implicated in the progression of multiple disease states, including cancer. RNA mA methylation is controlled by a multiprotein "writer" complex including the enzymatic factor methyltransferase-like protein 3 (METTL3) that regulates methylation and two "eraser" proteins, RNA demethylase ALKBH5 (ALKBH5) and fat mass- and obesity-associated protein (FTO), that demethylate mA in transcripts.
View Article and Find Full Text PDF