Mammalian target of rapamycin (mTOR) is a key regulator of cell growth acting via two independent targets, ribosomal protein S6 kinase 1 (S6K1) and 4EBP1. While each is known to regulate translational efficiency, the mechanism by which they control cell growth remains unclear. In addition to increased initiation of translation, the accelerated synthesis and accumulation of ribosomes are fundamental for efficient cell growth and proliferation. Using the mTOR inhibitor rapamycin, we show that mTOR is required for the rapid and sustained serum-induced activation of 45S ribosomal gene transcription (rDNA transcription), a major rate-limiting step in ribosome biogenesis and cellular growth. Expression of a constitutively active, rapamycininsensitive mutant of S6K1 stimulated rDNA transcription in the absence of serum and rescued rapamycin repression of rDNA transcription. Moreover, overexpression of a dominant-negative S6K1 mutant repressed transcription in exponentially growing NIH 3T3 cells. Rapamycin treatment led to a rapid dephosphorylation of the carboxy-terminal activation domain of the rDNA transcription factor, UBF, which significantly reduced its ability to associate with the basal rDNA transcription factor SL-1. Rapamycin-mediated repression of rDNA transcription was rescued by purified recombinant phosphorylated UBF and endogenous UBF from exponentially growing NIH 3T3 cells but not by hypophosphorylated UBF from cells treated with rapamycin or dephosphorylated recombinant UBF. Thus, mTOR plays a critical role in the regulation of ribosome biogenesis via a mechanism that requires S6K1 activation and phosphorylation of UBF.Cell growth (increased cell mass and size) is a prerequisite for proliferation (increased cell number), since a cell will divide only after it has reached a critical mass (38,49,55,58). Thus, factors that govern cell cycle progression must also regulate growth in an interrelated fashion. Cell growth is not however, unconditionally dependent on cell cycle progression, as mutations in the budding yeast Saccharomyces cerevisiae and the fruit fly Drosophila melanogaster that block or disrupt cell division do not necessarily arrest cell growth (34,44). Recent studies have demonstrated that cell growth and cell cycle progression in proliferating mammalian cells, like lower organisms, are also separable processes (8, 50, 63). Thus, detailed knowledge of the biochemical and molecular mechanisms governing cell size will be essential to understanding how the cell division cycle is coupled to growth and how this process is uncoupled during differentiation or is perturbed during diseases associated with deregulated growth. Our knowledge of cell cycle regulatory mechanisms has advanced considerably over the past decade. In contrast, information on the mechanisms of regulating cell growth in mammalian cells is limited.Increased protein synthesis is one of the major anabolic events required for the growth response (28). Recent studies suggest that one of the key nodal points upon which signaling pathwa...

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.

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.

We have located a locus, pgl, in Neisseria meningitidis strain NMB required for the glycosylation of class II pili. Between five and eight open reading frames (ORFs) (pglF, pglB, pglC, pglB2, orf2, orf3, orf8, and avtA) were present in the pgl clusters of different meningococcal isolates. The Class I pilus-expressing strains Neisseria gonorrhoeae MS11 and N. meningitidis MC58 each contain a pgl cluster in which orf2 and orf3 have been deleted. Strain NMB and other meningococcal isolates which express class II type IV pili contained pgl clusters in which pglB had been replaced by pglB2 and an additional novel ORF, orf8, had been inserted between pglB2 and pglC. Insertional inactivation of the eight ORFs of the pgl cluster of strain NMB showed that pglF, pglB2, pglC, and pglD, but not orf2, orf3, orf8, and avtA, were necessary for pilin glycosylation. Pilin glycosylation was not essential for resistance to normal human serum, as pglF and pglD mutants retained wild-type levels of serum resistance. Although pglB2 and pglC mutants were significantly sensitive to normal human serum under the experimental conditions used, subsequent examination of the encapsulation phenotypes revealed that pglB2 and pglC mutants expressed almost 50% less capsule than wild-type NMB. A mutation in orf3, which did not affect pilin glycosylation, also resulted in a 10% reduction in capsule expression and a moderately serum sensitive phenotype. On the basis of these results we suggest that pilin glycosylation may proceed via a lipid-linked oligosaccharide intermediate and that blockages in this pathway may interfere with capsular transport or assembly.

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 distribution of scarce healthcare resources is an increasingly important issue due to factors such as expensive 'high tech' medicine, longer life expectancies and the rising prevalence of chronic illness. Furthermore, in the current healthcare context lifestyle-related factors such as high blood pressure, tobacco use and obesity are believed to contribute significantly to the global burden of disease. As such, this paper focuses on an ongoing debate in the academic literature regarding the role of responsibility for illness in healthcare resource allocation: should patients with self-caused illness receive lower priority in access to healthcare resources? This paper critically describes the lower priority debate's 12 key arguments and maps out their relationships. This analysis reveals that most arguments have been refuted and that the debate has stalled and remains unresolved. In conclusion, we suggest progression could be achieved by inviting multidisciplinary input from a range of stakeholders for the development of evidence-based critical evaluations of existing arguments and the development of novel arguments, including the outstanding rebuttals.

To examine the type of published research regarding quality of life for cancer patients over two 24-month periods: 1995-1996 and 2005-2006. A computer-based literature search was conducted using Medline. Two random samples of 120 publications identified in 1995-1996 and in 2005-2006 were coded as data-based research, reviews or programme descriptions. Data-based publications were further coded as measurement, descriptive or intervention research. Intervention publications were coded as psychosocial- or biomedical-based. Psychosocial intervention papers were coded using Cochrane Review criteria. In 1995-1996, 419 publications were identified and 1271 publications in 2005-2006. The majority of publications were data-based. The proportion of types of publications (data-based, reviews or programme description/case report categories) did not change significantly over time. Descriptive research dominated data-based publication outputs in 1995-1996 and 2005-2006. The current approach to quality of life research for cancer patients may be less than optimal for providing successful development of knowledge, improving healthcare delivery and lessening the burden of suffering.

As a result of more people living with or surviving cancer, outputs for quality of life research may have increased over time to reflect the needs of the growing number of people affected by cancer. To determine if this is the case, the authors sought to examine the number and proportion of publications concerned with cancer patients' quality of life for four major cancer sites (breast, lung, prostate, colorectal) over five equal time periods (1985, 1990, 1995, 2000, 2005). A computer-based literature search using Medline and PsycINFO databases was undertaken. A comparison search with cancer-related biomedical terms was conducted. The results showed that the number of quality of life publications was substantially lower compared with biomedical publications over time, although the average annual relative increase in publications was greatest for quality of life. The total number of quality of life publications was greatest for breast cancer and lowest for colorectal cancer at all five time points. The relative increase over time of quality of life publications was greatest for prostate cancer and lowest for breast cancer. More research is needed regarding quality of life for cancer patients. Breast cancer has dominated quality of life research outputs despite a lower relative increase in publications over time compared with other cancer sites. There is need for debate among funding agencies and researchers to ensure research efforts are shared among cancer types.