RESUMEN
The endoribonuclease DICER1 plays an essential role in the microRNA (miRNA) biogenesis pathway, cleaving precursor miRNA (pre-miRNA) stem-loops to generate mature single-stranded miRNAs. Germline pathogenic variants (GPVs) in DICER1 result in DICER1 tumor predisposition syndrome (DTPS), a mainly childhood-onset tumor susceptibility disorder. Most DTPS-causing GPVs are nonsense or frameshifting, with tumor development requiring a second somatic missense hit that impairs the DICER1 RNase IIIb domain. Interestingly, germline DICER1 missense variants that cluster in the DICER1 Platform domain have been identified in some persons affected by tumors that also associate with DTPS. Here, we demonstrate that four of these Platform domain variants prevent DICER1 from producing mature miRNAs and as a result impair miRNA-mediated gene silencing. Importantly, we show that in contrast to canonical somatic missense variants that alter DICER1 cleavage activity, DICER1 proteins harboring these Platform variants fail to bind to pre-miRNA stem-loops. Taken together, this work sheds light upon a unique subset of GPVs causing DTPS and provides new insights into how alterations in the DICER1 Platform domain can impact miRNA biogenesis.
RESUMEN
Purpose: The COVID-19 pandemic has brought to light many systemic inequities in health care delivery. As medical communities work to address the disproportionate effects of COVID-19 on vulnerable populations, it is crucial to include refugees in the public health response. Language barriers, poor health literacy, and low socioeconomic status render refugee populations highly susceptible to negative outcomes from the COVID-19 pandemic. To better understand the refugee experience with COVID-19, we constructed and administered a survey among refugee populations in Houston, Texas. Methods: Our 49-question cross-sectional survey was administered to 44 participants in Arabic, Burmese, Dari, English, Kiswahili, Nepali, Spanish, or Urdu with the use of refugee resettlement case managers acting as translators. The survey encompassed three domains, including a general knowledge assessment of COVID-19, subjective experiences with COVID-19, and risk communication practices within refugee populations. Results: The majority of refugees surveyed admitted to worrying about the effects of COVID-19 on their community (88.6%). The negative consequences of the COVID-19 pandemic included financial adversity (65.1%) and significant disruption of children's education (62.8%). Although 50.0% of participants self-reported proficiency in English, translation services were used with 75.0% of participants to ensure full comprehension. Conclusions: The implications of our findings suggest that local refugee populations require heightened support during the COVID-19 pandemic. Tailored interventions should encompass comprehensive translation and interpretation services, financial assistance, and academic interventions for refugee youth.