PAX3-FOXO1 Drives Targetable Cell State-Dependent Metabolic Vulnerabilities in Rhabdomyosarcoma.

PAX3-FOXO1, an oncogenic transcription factor, drives a particularly aggressive subtype of rhabdomyosarcoma (RMS) by enforcing gene expression programs that support malignant cell states. Here, we showed that PAX3-FOXO1+ RMS cells exhibit altered pyrimidine metabolism and increased dependence on enzymes involved in de novo pyrimidine synthesis, including dihydrofolate reductase (DHFR). Consequently, PAX3-FOXO1+ cells displayed increased sensitivity to inhibition of DHFR by the chemotherapeutic drug methotrexate, and this dependence was rescued by provision of pyrimidine nucleotides.

Intracellular metabolic gradients dictate dependence on exogenous pyruvate.

During developmental transitions, cells frequently remodel metabolic networks, including changing reliance on metabolites such as glucose and glutamine to fuel intracellular metabolic pathways. Here we used embryonic stem (ES) cells as a model system to understand how changes in intracellular metabolic networks that characterize cell state transitions affect reliance on exogenous nutrients. We find that ES cells in the naive ground state of pluripotency increase uptake and reliance on exogenous pyruvate through the monocarboxylate transporter MCT1.

PAX3-FOXO1 drives targetable cell state-dependent metabolic vulnerabilities in rhabdomyosarcoma.

PAX3-FOXO1, an oncogenic transcription factor, drives a particularly aggressive subtype of rhabdomyosarcoma (RMS) by enforcing gene expression programs that support malignant cell states. Here we show that PAX3-FOXO1 RMS cells exhibit altered pyrimidine metabolism and increased dependence on enzymes involved in pyrimidine synthesis, including dihydrofolate reductase (DHFR). Consequently, PAX3-FOXO1 cells display increased sensitivity to inhibition of DHFR by the chemotherapeutic drug methotrexate, and this dependence is rescued by provision of pyrimidine nucleotides.

Correction: Problem-solving interventions and depression among adolescents and young adults: A systematic review of the effectiveness of problem-solving interventions in preventing or treating depression.

[This corrects the article DOI: 10.1371/journal.pone.

Problem-solving interventions and depression among adolescents and young adults: A systematic review of the effectiveness of problem-solving interventions in preventing or treating depression.

Problem-solving (PS) has been identified as a therapeutic technique found in multiple evidence-based treatments for depression. To further understand for whom and how this intervention works, we undertook a systematic review of the evidence for PS's effectiveness in preventing and treating depression among adolescents and young adults. We searched electronic databases (PsycINFO, Medline, and Cochrane Library) for studies published between 2000 and 2022.

Protocol for a systematic review of policies, programs or interventions designed to improve health and wellbeing of young people leaving the out-of-home care system.

Background: Relative to their counterparts in the general population, young people who leave, or transition out of, out-of-home (OOHC) arrangements commonly experience poorer outcomes across a range of indicators, including higher rates of homelessness, unemployment, reliance on public assistance, physical and mental health problems and contact with the criminal justice system. The age at which young people transition from OOHC varies between and within some countries, but for most, formal support ceases between the ages of 18 and 21. Programs designed to support transitions are generally available to young people toward the end of their OOHC placement, although some can extend beyond.

Interventions that address institutional child maltreatment: An evidence and gap map.

Background: Child maltreatment has serious short and long-term negative impacts for those experiencing it. Child maltreatment occurring in institutional settings has recently received substantial attention. However, evidence about the effectiveness of interventions that prevent, disclose, respond to, or treat maltreatment that has occurred in these environments is fragmented and can be difficult to access.

Nucleosome-positioning sequence repeats impact chromatin silencing in yeast minichromosomes.

Eukaryotic gene expression occurs in the context of structurally distinct chromosomal domains such as the relatively open, gene-rich, and transcriptionally active euchromatin and the condensed and gene-poor heterochromatin where its specific chromatin environment inhibits transcription. To study gene silencing by heterochromatin, we created a minichromosome reporter system where the gene silencer elements were used to repress the URA3 reporter gene. The minichromosome reporters were propagated in yeast Saccharomyces cerevisiae at a stable copy number.

A single heterochromatin boundary element imposes position-independent antisilencing activity in Saccharomyces cerevisiae minichromosomes.

Chromatin boundary elements serve as cis-acting regulatory DNA signals required to protect genes from the effects of the neighboring heterochromatin. In the yeast genome, boundary elements act by establishing barriers for heterochromatin spreading and are sufficient to protect a reporter gene from transcriptional silencing when inserted between the silencer and the reporter gene. Here we dissected functional topography of silencers and boundary elements within circular minichromosomes in Saccharomyces cerevisiae.

The N-terminus of Himar1 mariner transposase mediates multiple activities during transposition.

Mariner family transposons are perhaps the most widespread transposable elements of eukaryotes. While we are beginning to understand the precise mechanism of transposition of these elements, the structure of their transposases are still poorly understood. We undertook an extensive mutagenesis of the N-terminal third of the transposase of the Himar1 mariner transposon to begin the process of determining the structure and evolution of mariner transposases.