Pluripotency factors regulate the onset of Hox cluster activation in the early embryo.

Pluripotent cells are a transient population of the mammalian embryo dependent on transcription factors, such as OCT4 and NANOG, which maintain pluripotency while suppressing lineage specification. However, these factors are also expressed during early phases of differentiation, and their role in the transition from pluripotency to lineage specification is largely unknown. We found that pluripotency factors play a dual role in regulating key lineage specifiers, initially repressing their expression and later being required for their proper activation. We show that Oct4 is necessary for activation of HoxB genes during differentiation of embryonic stem cells and in the embryo. In addition, we show that the HoxB cluster is coordinately regulated by OCT4 binding sites located at the 3' end of the cluster. Our results show that core pluripotency factors are not limited to maintaining the precommitted epiblast but are also necessary for the proper deployment of subsequent developmental programs.

Post-COVID-19 syndrome. SARS-CoV-2 RNA detection in plasma, stool, and urine in patients with persistent symptoms after COVID-19.

BACKGROUND: There is a paucity of knowledge on the long-term outcome in patients diagnosed with COVID-19. We describe a cohort of patients with a constellation of symptoms occurring four weeks after diagnosis causing different degrees of reduced functional capacity. Although different hypothesis have been proposed to explain this condition like persistent immune activation or immunological dysfunction, to date, no physiopathological mechanism has been identified. Consequently, there are no therapeutic options besides symptomatic treatment and rehabilitation. METHODS: We evaluated patients with symptoms that persisted for at least 4 weeks after COVID-19. Epidemiological and clinical data were collected. Blood tests, including inflammatory markers, were conducted, and imaging studies made if deemed necessary. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse transcription polymerase chain reaction (RT-PCR) in plasma, stool, and urine were performed. Patients were offered antiviral treatment (compassionate use). RESULTS: We evaluated 29 patients who reported fatigue, muscle pain, dyspnea, inappropriate tachycardia, and low-grade fever. Median number of days from COVID-19 to positive RT-PCR in extra-respiratory samples was 55 (39-67). Previous COVID-19 was mild in 55% of the cases. Thirteen patients (45%) had positive plasma RT-PCR results and 51% were positive in at least one RT-PCR sample (plasma, urine, or stool). Functional status was severely reduced in 48% of the subjects. Eighteen patients (62%) received antiviral treatment. Improvement was seen in most patients (p = 0.000) and patients in the treatment group achieved better outcomes with significant differences (p = 0.01). CONCLUSIONS: In a cohort of COVID-19 patients with persistent symptoms, 45% of them have detectable plasma SARS-CoV-2 RNA. Our results indicate possible systemic viral persistence in these patients, who may benefit of antiviral treatment strategies.

Transitions in cell potency during early mouse development are driven by Notch.

The Notch signalling pathway plays fundamental roles in diverse developmental processes in metazoans, where it is important in driving cell fate and directing differentiation of various cell types. However, we still have limited knowledge about the role of Notch in early preimplantation stages of mammalian development, or how it interacts with other signalling pathways active at these stages such as Hippo. By using genetic and pharmacological tools in vivo, together with image analysis of single embryos and pluripotent cell culture, we have found that Notch is active from the 4-cell stage. Transcriptomic analysis in single morula identified novel Notch targets, such as early naïve pluripotency markers or transcriptional repressors such as TLE4. Our results reveal a previously undescribed role for Notch in driving transitions during the gradual loss of potency that takes place in the early mouse embryo prior to the first lineage decisions.