A bicistronic MAVS transcript highlights a class of truncated variants in antiviral immunity.

Bacterial and viral mRNAs are often polycistronic. Akin to alternative splicing, alternative translation of polycistronic messages is a mechanism to generate protein diversity and regulate gene function. Although a few examples exist, the use of polycistronic messages in mammalian cells is not widely appreciated. Here we report an example of alternative translation as a means of regulating innate immune signaling. MAVS, a regulator of antiviral innate immunity, is expressed from a bicistronic mRNA encoding a second protein, miniMAVS. This truncated variant interferes with interferon production induced by full-length MAVS, whereas both proteins positively regulate cell death. To identify other polycistronic messages, we carried out genome-wide ribosomal profiling and identified a class of antiviral truncated variants. This study therefore reveals the existence of a functionally important bicistronic antiviral mRNA and suggests a widespread role for polycistronic mRNAs in the innate immune system.

An essential mesenchymal function for miR-143/145 in intestinal epithelial regeneration.

Downregulation of the miR-143/145 microRNA (miRNA) cluster has been repeatedly reported in colon cancer and other epithelial tumors. In addition, overexpression of these miRNAs inhibits tumorigenesis, leading to broad consensus that they function as cell-autonomous epithelial tumor suppressors. We generated mice with deletion of miR-143/145 to investigate the functions of these miRNAs in intestinal physiology and disease in vivo. Although intestinal development proceeded normally in the absence of these miRNAs, epithelial regeneration after injury was dramatically impaired. Surprisingly, we found that miR-143/145 are expressed and function exclusively within the mesenchymal compartment of intestine. Defective epithelial regeneration in miR-143/145-deficient mice resulted from the dysfunction of smooth muscle and myofibroblasts and was associated with derepression of the miR-143 target Igfbp5, which impaired IGF signaling after epithelial injury. These results provide important insights into the regulation of epithelial wound healing and argue against a cell-autonomous tumor suppressor role for miR-143/145 in colon cancer.

An evolutionarily conserved ribosome-rescue pathway maintains epidermal homeostasis.

Ribosome-associated mRNA quality control mechanisms ensure the fidelity of protein translation1,2. Although these mechanisms have been extensively studied in yeast, little is known about their role in mammalian tissues, despite emerging evidence that stem cell fate is controlled by translational mechanisms3,4. One evolutionarily conserved component of the quality control machinery, Dom34 (in higher eukaryotes known as Pelota (Pelo)), rescues stalled ribosomes 5 . Here we show that Pelo is required for mammalian epidermal homeostasis. Conditional deletion of Pelo in mouse epidermal stem cells that express Lrig1 results in hyperproliferation and abnormal differentiation of these cells. By contrast, deletion of Pelo in Lgr5-expressing stem cells has no effect and deletion in Lgr6-expressing stem cells induces only a mild phenotype. Loss of Pelo results in accumulation of short ribosome footprints and global upregulation of translation, rather than affecting the expression of specific genes. Translational inhibition by rapamycin-mediated downregulation of mTOR (mechanistic target of rapamycin kinase) rescues the epidermal phenotype. Our study reveals that the ribosome-rescue machinery is important for mammalian tissue homeostasis and that it has specific effects on different stem cell populations.

Evaluation of obstructive sleep apnea among consecutive patients with all patterns of atrial fibrillation using WatchPAT home sleep testing.

BACKGROUND: Atrial fibrillation (AF) is the most common arrhythmia encountered in clinical practice and is associated with significant morbidity, mortality, and financial burden. Obstructive sleep apnea (OSA) is more common in individuals with AF and may impair the efficacy of rhythm control strategies including catheter ablation. However, the prevalence of undiagnosed OSA in all-comers with AF is unknown. DESIGN: This pragmatic, phase IV prospective cohort study will test 250-300 consecutive ambulatory AF patients with all patterns of atrial fibrillation (paroxysmal, persistent, and long-term persistent) and no prior sleep testing for OSA using the WatchPAT system, a disposable home sleep test (HST). The primary outcome of the study is the prevalence of undiagnosed OSA in all-comers with atrial fibrillation. RESULTS: Preliminary results from the initial pilot enrollment of approximately 15% (N = 38) of the planned sample size demonstrate a 79.0% prevalence of at least mild (AHI≥5) OSA or greater in consecutively enrolled patient with all patterns of AF. CONCLUSIONS: We report the design, methodology, and preliminary results of our study to define the prevalence of OSA in AF patients. This study will help inform approaches to OSA screening in patients with AF for which there is currently little practical guidance. CLINICAL TRIAL REGISTRATION: NCT05155813.

Slowed decay of mRNAs enhances platelet specific translation.

Platelets are anucleate cytoplasmic fragments that lack genomic DNA, but continue to synthesize protein using a pool of messenger RNAs (mRNAs), ribosomes, and regulatory small RNAs inherited from the precursor megakaryocyte (MK). The regulatory processes that shape the platelet transcriptome and the full scope of platelet translation have remained elusive. Using RNA sequencing (RNA-Seq) and ribosome profiling of primary human platelets, we show the platelet transcriptome encompasses a subset of transcripts detected by RNA-Seq analysis of in vitro-derived MK cells and that these platelet-enriched transcripts are broadly occupied by ribosomes. We use RNA-Seq of synchronized populations of in vitro-derived platelet-like particles to show that mRNA decay strongly shapes the nascent platelet transcriptome. Our data suggest that the decay of platelet mRNAs is slowed by the natural loss of the mRNA surveillance and ribosome rescue factor Pelota.

Breathless nights and heart flutters: Understanding the relationship between obstructive sleep apnea and atrial fibrillation.

There is an extraordinary and increasing global burden of atrial fibrillation (AF) and obstructive sleep apnea (OSA), two conditions that frequently accompany one another and that share underlying risk factors. Whether a causal pathophysiologic relationship connects OSA to the development and/or progression of AF, or whether shared risk factors promote both conditions, is unproven. With increasing recognition of the importance of controlling AF-related risk factors, numerous observational studies now highlight the potential benefits of OSA treatment in AF-related outcomes. Physicians are regularly faced with caring for this important and increasing population of patients despite a paucity of clinical guidance on the topic. Here, we review the clinical epidemiology and pathophysiology of AF and OSA with a focus on key clinical studies and major outstanding questions that should be addressed in future studies.

Ribosomopathies: There's strength in numbers.

Ribosomopathies are a group of human disorders most commonly caused by ribosomal protein haploinsufficiency or defects in ribosome biogenesis. These conditions manifest themselves as physiological defects in specific cell and tissue types. We review current molecular models to explain ribosomopathies and attempt to reconcile the tissue specificity of these disorders with the ubiquitous requirement for ribosomes in all cells. Ribosomopathies as a group are diverse in their origins and clinical manifestations; we use the well-described Diamond-Blackfan anemia (DBA) as a specific example to highlight some common features. We discuss ribosome homeostasis as an overarching principle that governs the sensitivity of specific cells and tissue types to ribosomal protein mutations. Mathematical models and experimental insights rationalize how even subtle shifts in the availability of ribosomes, such as those created by ribosome haploinsufficiency, can drive messenger RNA-specific effects on protein expression. We discuss recently identified roles played by ribosome rescue and recycling factors in regulating ribosome homeostasis.

Case of Secondary Tics Associated With Olanzapine in an Adult.

Atypical antipsychotic medications, such as risperidone, aripiprazole, and olanzapine, have utility in treating motor tics, particularly in Tourette syndrome. In rare cases, atypical antipsychotic medications have been associated with adult-onset motor tics. Such adverse drug reactions have been documented in response to quetiapine, aripiprazole, and amisulpride. Here, we report, to our knowledge, the first case of adult-onset motor tics related to olanzapine administration.

Dynamic Regulation of a Ribosome Rescue Pathway in Erythroid Cells and Platelets.

Protein synthesis continues in platelets and maturing reticulocytes, although these blood cells lack nuclei and do not make new mRNA or ribosomes. Here, we analyze translation in primary human cells from anucleate lineages by ribosome profiling and uncover a dramatic accumulation of post-termination unrecycled ribosomes in the 3' UTRs of mRNAs. We demonstrate that these ribosomes accumulate as a result of the natural loss of the ribosome recycling factor ABCE1 during terminal differentiation. Induction of the ribosome rescue factors PELO and HBS1L is required to support protein synthesis when ABCE1 levels fall and for hemoglobin production during blood cell development. Our observations suggest that this distinctive loss of ABCE1 in anucleate blood lineages could sensitize them to defects in ribosome homeostasis, perhaps explaining in part why genetic defects in the fundamental process of ribosome production ("ribosomopathies") often affect hematopoiesis specifically.