ZSWIM8 destabilizes many murine microRNAs and is required for proper embryonic growth and development.

MicroRNAs (miRNAs) pair to sites in mRNAs to direct the degradation of these RNA transcripts. Conversely, certain RNA transcripts can direct the degradation of particular miRNAs. This target-directed miRNA degradation (TDMD) requires the ZSWIM8 E3 ubiquitin ligase.

Massively parallel pooled screening reveals genomic determinants of nanoparticle delivery.

To accelerate the translation of cancer nanomedicine, we used an integrated genomic approach to improve our understanding of the cellular processes that govern nanoparticle trafficking. We developed a massively parallel screen that leverages barcoded, pooled cancer cell lines annotated with multiomic data to investigate cell association patterns across a nanoparticle library spanning a range of formulations with clinical potential. We identified both materials properties and cell-intrinsic features that mediate nanoparticle-cell association.

Rethinking the Physician-Scientist Pathway.

Physician-scientists have the potential to generate fundamental as well as translational breakthroughs. But many trainees who intend to pursue a hybrid career in research and patient care ultimately leave one or the other behind. In this Invited Commentary, the authors draw from their experience as early-career physician-scientists to frame physician-scientist training as having 2 phases: first, learning to think like a physician-scientist; second, learning to act like a physician-scientist.

Cystic Fibrosis and the Cells of the Airway Epithelium: What Are Ionocytes and What Do They Do?

Cystic fibrosis (CF) is caused by defects in an anion channel, the cystic fibrosis transmembrane conductance regulator (CFTR). Recently, a new airway epithelial cell type has been discovered and dubbed the pulmonary ionocyte. Unexpectedly, these ionocytes express higher levels of CFTR than any other airway epithelial cell type.

The Fast Literature Assessment and Review (FLARE) Initiative. A Collaborative Effort for Timely Literature Appraisal during the Coronavirus Disease Pandemic.

The emergence and worldwide spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused major disruptions to the healthcare system and medical education. In response, the scientific community has been acquiring, releasing, and publishing data at a remarkable pace. At the same time, medical practitioners are taxed with greater professional duties than ever before, making it challenging to stay current with the influx of medical literature.

Evidence-Based Management of the Critically Ill Adult With SARS-CoV-2 Infection.

Human infection by the novel viral pathogen SARS-CoV-2 results in a clinical syndrome termed Coronavirus Disease 2019 (COVID-19). Although the majority of COVID-19 cases are self-limiting, a substantial minority of patients develop disease severe enough to require intensive care. Features of critical illness associated with COVID-19 include hypoxemic respiratory failure, acute respiratory distress syndrome (ARDS), shock, and multiple organ dysfunction syndrome (MODS).

Lung Histopathology in Coronavirus Disease 2019 as Compared With Severe Acute Respiratory Sydrome and H1N1 Influenza: A Systematic Review.

Background: Patients with severe coronavirus disease 2019 (COVID-19) have respiratory failure with hypoxemia and acute bilateral pulmonary infiltrates, consistent with ARDS. Respiratory failure in COVID-19 might represent a novel pathologic entity.

Research Question: How does the lung histopathology described in COVID-19 compare with the lung histopathology described in SARS and H1N1 influenza?

Study Design And Methods: We conducted a systematic review to characterize the lung histopathologic features of COVID-19 and compare them against findings of other recent viral pandemics, H1N1 influenza and SARS.

Author Correction: A human ciliopathy reveals essential functions for NEK10 in airway mucociliary clearance.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Systemic Delivery of scAAV8-Encoded MiR-29a Ameliorates Hepatic Fibrosis in Carbon Tetrachloride-Treated Mice.

Fibrosis refers to the accumulation of excess extracellular matrix (ECM) components and represents a key feature of many chronic inflammatory diseases. Unfortunately, no currently available treatments specifically target this important pathogenic mechanism. MicroRNAs (miRNAs) are short, non-coding RNAs that post-transcriptionally repress target gene expression and the development of miRNA-based therapeutics is being actively pursued for a diverse array of diseases.

Tumor suppression by miR-26 overrides potential oncogenic activity in intestinal tumorigenesis.

Down-regulation of miR-26 family members has been implicated in the pathogenesis of multiple malignancies. In some settings, including glioma, however, miR-26-mediated repression of PTEN promotes tumorigenesis. To investigate the contexts in which the tumor suppressor versus oncogenic activity of miR-26 predominates in vivo, we generated miR-26a transgenic mice.

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.

Essential metabolic, anti-inflammatory, and anti-tumorigenic functions of miR-122 in liver.

miR-122, an abundant liver-specific microRNA (miRNA), regulates cholesterol metabolism and promotes hepatitis C virus (HCV) replication. Reduced miR-122 expression in hepatocellular carcinoma (HCC) correlates with metastasis and poor prognosis. Nevertheless, the consequences of sustained loss of function of miR-122 in vivo have not been determined.

Restitution of tumor suppressor microRNAs using a systemic nanovector inhibits pancreatic cancer growth in mice.

Mis-expression of microRNAs (miRNA) is widespread in human cancers, including in pancreatic cancer. Aberrations of miRNA include overexpression of oncogenic miRs (Onco-miRs) or downregulation of so-called tumor suppressor TSG-miRs. Restitution of TSG-miRs in cancer cells through systemic delivery is a promising avenue for pancreatic cancer therapy.

Repression of the miR-143/145 cluster by oncogenic Ras initiates a tumor-promoting feed-forward pathway.

Although activating mutations in RAS oncogenes are known to result in aberrant signaling through multiple pathways, the role of microRNAs (miRNAs) in the Ras oncogenic program remains poorly characterized. Here we demonstrate that Ras activation leads to repression of the miR-143/145 cluster in cells of human, murine, and zebrafish origin. Loss of miR-143/145 expression is observed frequently in KRAS mutant pancreatic cancers, and restoration of these miRNAs abrogates tumorigenesis.

Quantification of global microRNA abundance by selective isotachophoresis.

We here present and demonstrate a novel technique based on isotachophoresis (ITP) for the quantification of global microRNA (miRNA) abundance in total RNA. We leverage the selectivity of ITP to concentrate miRNA and exclude longer RNA molecules from the focused zone. We designed a novel ITP strategy where we initially establish three contiguous zones of sieving polymer, electrolyte, and denaturant concentrations.

Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model.

Therapeutic strategies based on modulation of microRNA (miRNA) activity hold great promise due to the ability of these small RNAs to potently influence cellular behavior. In this study, we investigated the efficacy of a miRNA replacement therapy for liver cancer. We demonstrate that hepatocellular carcinoma (HCC) cells exhibit reduced expression of miR-26a, a miRNA that is normally expressed at high levels in diverse tissues.

Abate and switch: miR-145 in stem cell differentiation.

MicroRNAs have been implicated as regulators of embryonic stem (ES) cell self-renewal and pluripotency. In this issue, Xu et al. (2009) demonstrate that miR-145 facilitates ES cell differentiation by repressing the core pluripotency factors OCT4, SOX2, and KLF4, thereby silencing the self-renewal program.

Lin-28B transactivation is necessary for Myc-mediated let-7 repression and proliferation.

Direct control of microRNA (miRNA) expression by oncogenic and tumor suppressor networks results in frequent dysregulation of miRNAs in cancer cells and contributes to tumorigenesis. We previously demonstrated that activation of the c-Myc oncogenic transcription factor (Myc) broadly influences miRNA expression and in particular leads to widespread miRNA down-regulation. miRNA transcripts repressed by Myc include several with potent tumor suppressor activity such as miR-15a/16-1, miR-34a, and let-7 family members.