UBF levels determine the number of active ribosomal RNA genes in mammals

In mammals, the mechanisms regulating the number of active copies of the ∼200 ribosomal RNA (rRNA) genes transcribed by RNA polymerase I are unclear. We demonstrate that depletion of the transcription factor upstream binding factor (UBF) leads to the stable and reversible methylation-independent silencing of rRNA genes by promoting histone H1–induced assembly of transcriptionally inactive chromatin. Chromatin remodeling is abrogated by the mutation of an extracellular signal-regulated kinase site within the high mobility group box 1 domain of UBF1, which is required for its ability to bend and loop DNA in vitro. Surprisingly, rRNA gene silencing does not reduce net rRNA synthesis as transcription from remaining active genes is increased. We also show that the active rRNA gene pool is not static but decreases during differentiation, correlating with diminished UBF expression. Thus, UBF1 levels regulate active rRNA gene chromatin during growth and differentiation

Clinician gate-keeping in clinical research is not ethically defensible: an analysis

Clinician gate-keeping is the process whereby healthcare providers prevent access to eligible patients for research recruitment. This paper contends that clinician gate-keeping violates three principles that underpin international ethical guidelines: respect for persons or autonomy; beneficence or a favourable balance of risks and potential benefits; and justice or a fair distribution of the benefits and burdens of research. In order to stimulate further research and debate, three possible strategies are also presented to eliminate gate-keeping: partnership with professional researchers; collaborative research design and clinician education

The development of a nurse-led psychosocial intervention with peer support for women being treated with radiotherapy for gynaecological cancer (GC)

OBJECTIVES: Radiotherapy for GC has numerous potentially distressing side effects which impact on psychosocial functioning and intimate relationships. Distress associated with diagnosis and treatment can be ameliorated by comprehensive preparation for treatment and addressing informational, physical and psychosocial needs during treatment. The proposed intervention combines tailored specialist nursing consultations with peer support (GC survivor). The objective is to develop, refine and pre-test an intervention package to ensure its relevance and acceptability to patients and clinicians. METHOD: Drawing on extensive literature reviews and consumer input, a 3-stage process for developing complex interventions, based on UK Medical Research Council Framework, was used. This comprised: (1) Problem definition: the nature and extent of unmet supportive care needs. (2) Refining the intervention by iterative clinician, and consumer review: evidence-based content; complexity and tailoring; delivery and dose; and integrity. (3) Pre-testing the intervention with 10 women and conduct interviews to assist in finalizing the intervention. RESULTS: The list of unmet needs was combined with best available evidence for self-care to draft two intervention manuals. The nurse manual specified the content of three nurse-led consultations at the pre-, mid- and end of treatment to provide tailored information, self-care coaching and MDT carecoordination. The peer manual specified the content of five phone calls (pre-, mid-, end of treatment and twice post-treatment) to provide psychosocial support and encourage adherence to the self-care plan. CONCLUSIONS: The intervention package was well-received by consumers and clinicians. The consumer feedback provided indicates that access to accurate and timely medical and self-care information from nurses is critically important, and the unique perspective of a peer lends authenticity to support that facilitates sharing, practical, emotional and meaning-based coping. The next stage is to conduct a multi-site RCT to test the effectiveness of the intervention to reduce psychological distress, psychosocial needs, psychosexual difficulties and symptoms

MAD1 and c-MYC regulate UBF and rDNA transcription during granulocyte differentiation

The regulation of cell mass (cell growth) is often tightly coupled to the cell division cycle (cell proliferation). Ribosome biogenesis and the control of rDNA transcription through RNA polymerase I are known to be critical determinants of cell growth. Here we show that granulocytic cells deficient in the c-MYC antagonist MAD1 display increased cell volume, rDNA transcription and protein synthesis. MAD1 repressed and c-MYC activated rDNA transcription in nuclear run-on assays. Repression of rDNA transcription by MAD1 was associated with its ability to interact directly with the promoter of upstream binding factor (UBF), an rDNA regulatory factor. Conversely, c-MYC activated transcription from the UBF promoter. Using siRNA, UBF was shown to be required for c-MYC-induced rDNA transcription. These data demonstrate that MAD1 and c-MYC reciprocally regulate rDNA transcription, providing a mechanism for coordination of ribosome biogenesis and cell growth under conditions of sustained growth inhibition such as granulocyte differentiation