Cellular dsRNA interactome captured by K1 antibody reveals the regulatory map of exogenous RNA sensing.

RNA-binding proteins (RBPs) provide a critical post-transcriptional regulatory layer in determining RNA fate. Currently, UV crosslinking followed by oligo-dT pull-down is the gold standard in identifying the RBP repertoire of poly-adenylated RNAs, but such method is ineffective in capturing RBPs that recognize double-stranded RNAs (dsRNAs). Here, we utilize anti-dsRNA K1 antibody immunoprecipitation followed by quantitative mass spectrometry to comprehensively identify RBPs bound to cellular dsRNAs without external stimulus.

Double-Stranded RNA-Based Method for Diagnosing Severe Fever with Thrombocytopenia.

: This study explores the potential of using elevated levels of blood double-stranded RNA (dsRNA) as a diagnostic tool for severe fever with thrombocytopenia syndrome (SFTS) infection. : Blood samples from SFTS patients were collected, dsRNA was purified, and total dsRNA expression was quantitatively analyzed using a spiropyran-based method. Comparative analysis was performed using blood samples from healthy individuals and scrub typhus patients with similar symptoms.

Targeting mitochondrial RNAs enhances the efficacy of the DNA-demethylating agents.

Hypomethylating agents (HMAs) such as azacytidine and decitabine are FDA-approved chemotherapy drugs for hematologic malignancy. By inhibiting DNA methyltransferases, HMAs reactivate tumor suppressor genes (TSGs) and endogenous double-stranded RNAs (dsRNAs) that limit tumor growth and trigger apoptosis via viral mimicry. Yet, HMAs show limited effects in many solid tumors despite the strong induction of TSGs and dsRNAs.

RNA 5-methylcytosine marks mitochondrial double-stranded RNAs for degradation and cytosolic release.

Mitochondria are essential regulators of innate immunity. They generate long mitochondrial double-stranded RNAs (mt-dsRNAs) and release them into the cytosol to trigger an immune response under pathological stress conditions. Yet the regulation of these self-immunogenic RNAs remains largely unknown.

SLIRP promotes autoimmune diseases by amplifying antiviral signaling via positive feedback regulation.

The abnormal innate immune response is a prominent feature underlying autoimmune diseases. One emerging factor that can trigger dysregulated immune activation is cytosolic mitochondrial double-stranded RNAs (mt-dsRNAs). However, the mechanism by which mt-dsRNAs stimulate immune responses remains poorly understood.

Live-Cell Imaging of MicroRNA Expression via Photoinduced Electron Transfer Controlled by Catalytic Hairpin Assembly.

MicroRNAs (miRNAs) serve as emerging biomarkers for a range of diseases, and their quantitative analysis draws increasing attention. Yet, current invasive methods limit continuous tracking within living cells. To overcome this, a nonenzymatic DNA-based nanoprobe is developed for dynamic, noninvasive miRNA tracking via live-cell imaging.

Inverted Alu repeats: friends or foes in the human transcriptome.

Alu elements are highly abundant primate-specific short interspersed nuclear elements that account for ~10% of the human genome. Due to their preferential location in gene-rich regions, especially in introns and 3' UTRs, Alu elements can exert regulatory effects on the expression of both host and neighboring genes. When two Alu elements with inverse orientations are positioned in close proximity, their transcription results in the generation of distinct double-stranded RNAs (dsRNAs), known as inverted Alu repeats (IRAlus).

Alternative polyadenylation determines the functional landscape of inverted Alu repeats.

Inverted Alu repeats (IRAlus) are abundantly found in the transcriptome, especially in introns and 3' untranslated regions (UTRs). Yet, the biological significance of IRAlus embedded in 3' UTRs remains largely unknown. Here, we find that 3' UTR IRAlus silences genes involved in essential signaling pathways.

Mitochondrial nucleic acids in innate immunity and beyond.

Mitochondria participate in a wide range of cellular processes. One essential function of mitochondria is to be a platform for antiviral signaling proteins during the innate immune response to viral infection. Recently, studies have revealed that mitochondrion-derived DNAs and RNAs are recognized as non-self molecules and act as immunogenic ligands.

Resveratrol Attenuates the Mitochondrial RNA-Mediated Cellular Response to Immunogenic Stress.

Human mitochondria contain a circular genome that encodes 13 subunits of the oxidative phosphorylation system. In addition to their role as powerhouses of the cells, mitochondria are also involved in innate immunity as the mitochondrial genome generates long double-stranded RNAs (dsRNAs) that can activate the dsRNA-sensing pattern recognition receptors. Recent evidence shows that these mitochondrial dsRNAs (mt-dsRNAs) are closely associated with the pathogenesis of human diseases that accompany inflammation and aberrant immune activation, such as Huntington's disease, osteoarthritis, and autoimmune Sjögren's syndrome.

Multi-targeted therapy resistance via drug-induced secretome fucosylation.

Cancer secretome is a reservoir for aberrant glycosylation. How therapies alter this post- translational cancer hallmark and the consequences thereof remain elusive. Here, we show that an elevated secretome fucosylation is a pan-cancer signature of both response and resistance to multiple targeted therapies.

Analysis of mitochondrial double-stranded RNAs in human cells.

Human mitochondrial genome is transcribed bidirectionally, generating long complementary RNAs that can form double-stranded RNAs (mt-dsRNAs). When released to the cytosol, these mt-dsRNAs can activate antiviral signaling. Here, we present a detailed protocol for the analysis of mt-dsRNA expression.

Double-stranded RNA induction asa potential dynamic biomarkerfor DNA-demethylating agents.

Hypomethylating agents (HMAs), such as azacitidine and decitabine, induce cancer cell death by demethylating DNAs to promote the expression of tumor-suppressor genes. HMAs also reactivate the transcription of endogenous double-stranded RNAs (dsRNAs) that trigger the innate immune response and subsequent apoptosis via viral mimicry. However, the expression patterns of endogenous dsRNAs and their relevance in the efficacy of HMAs remain largely uninvestigated.

Mitochondrial double-stranded RNAs govern the stress response in chondrocytes to promote osteoarthritis development.

Protein kinase R (PKR) is an immune response protein that becomes activated by double-stranded RNAs (dsRNAs). PKR overactivation is associated with degenerative diseases with inflammation, including osteoarthritis (OA), but the dsRNA activator remains largely unknown. Here, we find that mitochondrial dsRNA (mt-dsRNA) expression and its cytosolic efflux are facilitated in chondrocytes under OA-eliciting conditions, leading to innate immune activation.

High-Intensity Aerobic Exercise Suppresses Cancer Growth by Regulating Skeletal Muscle-Derived Oncogenes and Tumor Suppressors.

High-intensity aerobic exercise (90% of the maximal heart rate) can effectively suppress cancer cell proliferation . However, the molecular effects of exercise and its relevance to cancer prevention remain uninvestigated. In this study, mice with colorectal cancer were subjected to high-intensity aerobic exercise, and mRNA-seq analysis was performed on the heart, lungs, and skeletal muscle tissues to analyze the genome-wide molecular effects of exercise.

Potential toxicity of inorganic ions in particulate matter: Ion permeation in lung and disruption of cell metabolism.

Exposure to ambient particulate matter (PM) is associated with adverse health effects. Yet, due to the complexity of its chemical composition, the molecular effects of PM exposure and the mechanism of PM-mediated toxicity remain largely unknown. Here, we show that water-soluble inorganics such as nitrate and sulfate ions, rather than PM itself, rapidly penetrate the lung surfactant barrier to the alveolar region and perturb gene expression in the lungs.

Dual Targeting of EGFR with PLK1 Exerts Therapeutic Synergism in Taxane-Resistant Lung Adenocarcinoma by Suppressing ABC Transporters.

To overcome the limitations of chemoresistance, combination therapies using druggable targets have been investigated. Our previous studies led us to hypothesize that the downregulation of PLK1 expression or activity can be one strategy to overcome the hurdles of taxane resistance by the downregulation of ABC transporters. To explore this, various versions of PLK1 including a constitutively active version, kinase-dead form, and polo-box domain mutant were expressed in paclitaxel-resistant lung adenocarcinoma (LUAD).

The Diagnostic Performance of Early Sjögren's Syndrome Autoantibodies in Juvenile Sjögren's Syndrome: The University of Florida Pediatric Cohort Study.

Objectives: The aim of this study was to evaluate the clinical validity of early Sjögren's syndrome (SS) autoantibodies (eSjA), which were originally marketed for early diagnosis of SS, for juvenile SS (JSS) in a recently identified pediatric cohort.

Methods: A total of 105 symptomatic subjects with eSjA results available were evaluated at the Center for Orphaned Autoimmune Disorders at the University of Florida and enrolled for this study. JSS diagnosis was based on the 2016 ACR/EULAR SS criteria.

Chemotherapy confers a conserved secondary tolerance to EGFR inhibition via AXL-mediated signaling bypass.

Drug resistance remains the major culprit of therapy failure in disseminated cancers. Simultaneous resistance to multiple, chemically different drugs feeds this failure resulting in cancer relapse. Here, we investigate co-resistance signatures shared between antimitotic drugs (AMDs) and inhibitors of receptor tyrosine kinases (RTKs) to probe mechanisms of secondary resistance.

Noncanonical immune response to the inhibition of DNA methylation by Staufen1 via stabilization of endogenous retrovirus RNAs.

DNA-methyltransferase inhibitors (DNMTis), such as azacitidine and decitabine, are used clinically to treat myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Decitabine activates the transcription of endogenous retroviruses (ERVs), which can induce immune response by acting as cellular double-stranded RNAs (dsRNAs). Yet, the posttranscriptional regulation of ERV dsRNAs remains uninvestigated.

A novel method to detect mutation in DNA by utilizing exponential amplification reaction triggered by the CRISPR-Cas9 system.

We, herein, describe a novel method to detect mutation in DNA by utilizing exponential amplification reaction (EXPAR) triggered by clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9, called CRISPR-EXPAR. The CRISPR system consisting of two Cas9/sgRNA complexes was designed to cut out a specific mutation region within the target DNA, which would consequently promote EXPAR by continuously repeated extension and nicking reactions. As a consequence, a large number of final EXPAR products, which can be monitored through duplex-specific fluorescent staining, are produced.

DeepRegularizer: Rapid Resolution Enhancement of Tomographic Imaging Using Deep Learning.

Optical diffraction tomography measures the three-dimensional refractive index map of a specimen and visualizes biochemical phenomena at the nanoscale in a non-destructive manner. One major drawback of optical diffraction tomography is poor axial resolution due to limited access to the three-dimensional optical transfer function. This missing cone problem has been addressed through regularization algorithms that use a priori information, such as non-negativity and sample smoothness.

Single-cell analysis of AIMP2 splice variants informs on drug sensitivity and prognosis in hematologic cancer.

Aminoacyl-tRNA synthetase-interacting multifunctional protein 2 (AIMP2) is a non-enzymatic component required for the multi-tRNA synthetase complex. While exon 2 skipping alternatively spliced variant of AIMP2 (AIMP2-DX2) compromises AIMP2 activity and is associated with carcinogenesis, its clinical potential awaits further validation. Here, we found that AIMP2-DX2/AIMP2 expression ratio is strongly correlated with major cancer signaling pathways and poor prognosis, particularly in acute myeloid leukemia (AML).