EndoVIA for quantifying A-to-I editing and mapping the subcellular localization of edited transcripts.

Adenosine-to-inosine (A-to-I) editing, catalyzed by adenosine deaminases acting on RNA (ADARs), is a prevalent post-transcriptional modification that is vital for numerous biological functions. Given that this modification impacts global gene expression, RNA localization, and innate cellular immunity, dysregulation of A-to-I editing has unsurprisingly been linked to a variety of cancers and other diseases. However, our current understanding of the underpinning mechanisms that connect dysregulated A-to-I editing and disease processes remains limited.

A probe-based capture enrichment method for detection of A-to-I editing in low abundance transcripts.

Exactly two decades ago, the ability to use high-throughput RNA sequencing technology to identify sites of editing by ADARs was employed for the first time. Since that time, RNA sequencing has become a standard tool for researchers studying RNA biology and led to the discovery of RNA editing sites present in a multitude of organisms, across tissue types, and in disease. However, transcriptome-wide sequencing is not without limitations.

CellREADR: An ADAR-based RNA sensor-actuator device.

RNAs are central mediators of genetic information flow and gene regulation that underlie diverse cell types and cell states across species. Thus, methods that can sense and respond to RNA profiles in living cells will have broad applications in biology and medicine. CellREADR - Cell access through RNA sensing by Endogenous ADAR (adenosine deaminase acting on RNA), is a programmable RNA sensor-actuator technology that couples the detection of a cell-defining RNA to the translation of an effector protein to monitor and manipulate the cell.

Structural analysis of human ADAR2-RNA complexes by X-ray crystallography.

Adenosine deaminases acting on RNAs (ADARs) are a class of RNA editing enzymes found in metazoa that catalyze the hydrolytic deamination of adenosine to inosine in duplexed RNA. Inosine is a nucleotide that can base pair with cytidine, therefore, inosine is interpreted by cellular processes as guanosine. ADARs are functionally important in RNA recoding events, RNA structure modulation, innate immunity, and can be harnessed for therapeutically-driven base editing to treat genetic disorders.

En masse evaluation of RNA guides (EMERGe) for ADARs.

Adenosine Deaminases Acting on RNA (ADARs) convert adenosine to inosine in duplex RNA, and through the delivery of guide RNAs, can be directed to edit specific adenosine sites. As ADARs are endogenously expressed in humans, their editing capacities hold therapeutic potential and allow us to target disease-relevant sequences in RNA through the rationale design of guide RNAs. However, current design principles are not suitable for difficult-to-edit target sites, posing challenges to unlocking the full therapeutic potential of this approach.

Retinoids and retinoid-binding proteins: Unexpected roles in metabolic disease.

Alterations in tissue expression levels of both retinol-binding protein 2 (RBP2) and retinol-binding protein 4 (RBP4) have been associated with metabolic disease, specifically with obesity, glucose intolerance and hepatic steatosis. Our laboratories have shown that this involves novel pathways not previously considered as possible linkages between impaired retinoid metabolism and metabolic disease development. We have established both biochemically and structurally that RBP2 binds with very high affinity to very long-chain unsaturated 2-monoacylglycerols like the canonical endocannabinoid 2-arachidonoyl glycerol (2-AG) and other endocannabinoid-like substances.

Multiple roles for retinoid signaling in craniofacial development.

Retinoic acid (RA) signaling plays multiple essential roles in development of the head and face. Animal models with mutations in genes involved in RA signaling have enabled understanding of craniofacial morphogenic processes that are regulated by the retinoid pathway. During craniofacial morphogenesis RA signaling is active in spatially restricted domains defined by the expression of genes involved in RA production and RA breakdown.

Vitamin A supply in the eye and establishment of the visual cycle.

Animals perceiving light through visual pigments have evolved pathways for absorbing, transporting, and metabolizing the precursors essential for synthesis of their retinylidene chromophores. Over the past decades, our understanding of this metabolism has grown significantly. Through genetic manipulation, researchers gained insights into the metabolic complexity of the pathways mediating the flow of chromophore precursors throughout the body, and their enrichment within the eyes.

Retinoid signaling in pancreas development, islet function, and disease.

All-trans retinoic acid (ATRA) signaling is essential in numerous different biological contexts. This review highlights the diverse roles of ATRA during development, function, and diseases of the pancreas. ATRA is essential to specify pancreatic progenitors from gut tube endoderm, endocrine and exocrine differentiation, and adult islet function.

The multifaceted roles of retinoids in eye development, vision, and retinal degenerative diseases.

Vitamin A (all-trans-retinol; at-Rol) and its derivatives, known as retinoids, have been adopted by vertebrates to serve as visual chromophores and signaling molecules, particularly in the eye/retina. Few tissues rely on retinoids as heavily as the retina, and the study of genetically modified mouse models with deficiencies in specific retinoid-metabolizing proteins has allowed us to gain insight into the unique or redundant roles of these proteins in at-Rol uptake and storage, or their downstream roles in retinal development and function. These processes occur during embryogenesis and continue throughout life.

Retinoic acid homeostasis and disease.

Retinoids, particularly all-trans-retinoic acid (ATRA), play crucial roles in various physiological processes, including development, immune response, and reproduction, by regulating gene transcription through nuclear receptors. This review explores the biosynthetic pathways, homeostatic mechanisms, and the significance of retinoid-binding proteins in maintaining ATRA levels. It highlights the intricate balance required for ATRA homeostasis, emphasizing that both excess and deficiency can lead to severe developmental and health consequences.

The action of retinoic acid on spermatogonia in the testis.

For mammalian spermatogenesis to proceed normally, it is essential that the population of testicular progenitor cells, A undifferentiated spermatogonia (A), undergoes differentiation during the A to A1 transition that occurs at the onset of spermatogenesis. The commitment of the A population to differentiation and leaving a quiescent, stem-like state gives rise to all the spermatozoa produced across the lifespan of an individual, and ultimately determines male fertility. The action of all-trans retinoic acid (atRA) on the A population is the determining factor that induces this change.

Rethinking retinoic acid self-regulation: A signaling robustness network approach.

All-trans retinoic acid (ATRA) signaling is a major pathway regulating numerous differentiation, proliferation, and patterning processes throughout life. ATRA biosynthesis depends on the nutritional availability of vitamin A and other retinoids and carotenoids, while it is sensitive to dietary and environmental toxicants. This nutritional and environmental influence requires a robustness response that constantly fine-tunes the ATRA metabolism to maintain a context-specific, physiological range of signaling levels.

Early retinoic acid signaling organizes the body axis and defines domains for the forelimb and eye.

All-trans RA (ATRA) is a small molecule derived from retinol (vitamin A) that directly controls gene expression at the transcriptional level by serving as a ligand for nuclear ATRA receptors. ATRA is produced by ATRA-generating enzymes that convert retinol to retinaldehyde (retinol dehydrogenase; RDH10) followed by conversion of retinaldehyde to ATRA (retinaldehyde dehydrogenase; ALDH1A1, ALDH1A2, or ALDH1A3). Determining what ATRA normally does during vertebrate development has been challenging as studies employing ATRA gain-of-function (RA treatment) often do not agree with genetic loss-of-function studies that remove ATRA via knockouts of ATRA-generating enzymes.

Psychometric Properties of a Questionnaire for Assessing the Extent and Severity of the Concerns of People With an Implanted Cardioverter-Defibrillator.

Considering the numerous concerns patients express about having implantable cardioverter-defibrillators (ICDs) and the potential clinical implications of these concerns, it is essential to develop a valid and reliable measure of ICD-related concerns. The implantable cardioverter-defibrillator concerns (ICDC) questionnaire was initially designed for ICD recipients in England to assess and address these concerns. However, it remains uncertain whether this questionnaire possesses similar measurement properties and is suitable for ICD recipients in the United States.

Evaluating the Impact of an Educational Intervention on Nursing Labor Support Practices and Cesarean Birth Rates.

Over 30% of births in the United States occur via cesarean section despite increased risks to the birthing person and neonate. Evidence-based nursing practice related to fetal monitoring, patient positioning, and management of the second stage of labor can decrease the incidence of cesarean birth. The objective is to decrease the cesarean birth rate by 3% in a Midwestern suburban hospital.

A Community Initiative to Increase Colorectal Cancer Knowledge, Awareness, and Intent to Screen in an Underserved Region.

Colorectal cancer (CRC) is a leading cause of cancer-related deaths in the United States despite the availability of effective preventive screening. This project was designed as a community awareness initiative to increase CRC awareness, knowledge, and intent to discuss and complete CRC screening. This quasi-experimental study had a QI focus and used a convenience sample in a public setting assessing CRC awareness, knowledge, and intent to discuss and complete screening after participating in an inflatable colon tour.

A year in review: new treatments and expanded indications in dermatology in 2024.

Methods: A literature search was conducted on Drugs@FDA: FDA-Approved Drugs for the year 2024 to identify new dermatologic treatments.

Results: In 2024, the FDA approved seven new dermatologic therapies and expanded the indications for seven current therapies. These therapies treat conditions such as atopic dermatitis, hidradenitis suppurativa, prurigo nodularis, molluscum contagiosum, and alopecia areata, among others.

Evaluation of a disease-state education program in asthma: Application of the Knowledge-to-Action Framework.

Background: In patients with asthma, bronchoconstriction and airway inflammation both contribute to airway narrowing and airflow limitations, which lead to symptoms and exacerbations. Short-acting beta 2-agonist (SABA)-only rescue therapy addresses only bronchoconstriction and is associated with increased morbidity and mortality. Current asthma management guidelines recommend concomitant treatment of symptoms and inflammation with a fast-acting bronchodilator and inhaled corticosteroid (ICS) as rescue therapy for patients 12 years of age.

Internet-based cognitive behavioral therapy for alcohol use disorder: A systematic review of evidence and future potential.

Introduction: While cognitive behavioral therapy (CBT) remains a highly effective psychotherapy approach for managing Alcohol Use Disorder (AUD), its potential is hindered by workforce shortages and access barriers. In response to these challenges, Internet-Based Cognitive Behavioral Therapy (iCBT) has emerged as an innovative solution that integrates the core CBT structure with technology. In iCBT, educational materials, therapist communication and progress dashboards can be centralized in a digital format, and delivered in a self-guided, therapist-guided or blended approach.

Supporting Unhealthy Substance use care Through a whole person Approach and user centered INtegration into primary care (SUSTAIN): Study protocol for a type 2 hybrid effectiveness-implementation trial.

Background: Unhealthy substance use (USU) is common and ranges from use above guideline-recommended levels to severe substance use disorder. USU results in substantial morbidity and mortality yet primary care practices rarely systematically screen, diagnose, and treat USU. Supporting Unhealthy Substance use care Through a whole person Approach and user centered INtegration into primary care (SUSTAIN) tests whether the implementation of a co-designed change package for USU improves patient function.

Biochemical, structural, and cellular characterization of S-but-3-yn-2-ylglycine as a mechanism-based covalent inactivator of the flavoenzyme proline dehydrogenase.

The mitochondrial flavoenzymes proline dehydrogenase (PRODH) and hydroxyproline dehydrogenase (PRODH2) catalyze the first steps of proline and hydroxyproline catabolism, respectively. The enzymes are targets for chemical probe development because of their roles in cancer cell metabolism (PRODH) and primary hyperoxaluria (PRODH2). Mechanism-based inactivators of PRODH target the FAD by covalently modifying the N5 atom, with N-propargylglycine (NPPG) being the current best-in-class of this type of probe.