RNA interference (RNAi) is now an umbrella term referring to post-transcriptional gene silencing mediated by either degradation or translation arrest of target RNA. This process is initiated by double-stranded RNA with sequence homology driving specificity. The discovery that 21-23 nucleotide RNA duplexes (small-interfering RNAs, siRNAs) mediate RNAi in mammalian cells opened the door to the therapeutic use of siRNAs. While much work remains to optimize delivery and maintain specificity, the therapeutic advantages of siRNAs for treatment of viral infection, dominant disorders, cancer, and neurological disorders show great promise. Gene Therapy (2005) 12, 5-11.

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Cortical progenitors begin to interpret leukemia inhibitory factor (LIF) and bone morphogenetic protein (BMP) as astrocyte-inducing signals during late embryonic cortical development, coincident with an increase in their expression of epidermal growth factor receptors (EGFRs). To determine whether the developmental change in EGFRs regulates the change in responsiveness to LIF and BMP, we analyzed cortical progenitors induced to express EGFRs prematurely and progenitors from late embryonic EGFR-null cortex. Premature elevation of EGFRs conferred premature competence to interpret LIF, but not BMP, as an astrocyte-inducing signal. EGFR-null progenitors from late embryonic cortex did not interpret LIF as an astrocyte-inducing signal but responded to BMP4. LIF responsiveness in EGFR-null cells was rescued by the addition of EGFRs but not by the stimulation of fibroblast growth factor receptors. Astrocyte differentiation induced by LIF depends on signal transducer and activator of transcription 3 (STAT3). We show that the level of STAT3 increases during late embryonic development in a subset of progenitors. EGFRs regulate this change in STAT3 and increase STAT3 phosphorylation in response to LIF. Increasing STAT3 prematurely with a retrovirus also increased the phosphorylation of STAT3 by LIF. In contrast to the finding with EGFRs, however, increasing STAT3 did not cause LIF to induce astrocytes, although it reduced expression of the neurogenic factor PAX6 (paired box gene 6 ). Our findings show that developmental changes in EGFRs regulate the competence of progenitors to interpret LIF as an astrocyte-inducing signal. EGFRs elevate STAT3 expression and increase its phosphorylation by LIF, but this is not sufficient to change LIF responsiveness to astrocyte induction, suggesting that EGFRs also regulate LIF responsiveness downstream of STAT3.

In this study, many healthcare workers demonstrated a lack of awareness and understanding of the vaccine, especially in relation to its benefits and side-effects. Relevance to clinical practice. Vaccinating healthcare workers against influenza can reduce staff sickness during times of winter pressure as well as reducing mortality in frail, older hospitalized patients. It is therefore important that hospitals maximize vaccine uptake by increasing awareness and promoting the benefits of influenza vaccine amongst healthcare workers as well as ensuring that all staff have the opportunity to receive the vaccine.

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