A novel role for GSK3β as a modulator of Drosha microprocessor activity and MicroRNA biogenesis

Regulation of microRNA (miR) biogenesis is complex and stringently controlled. Here, we identify the kinase GSK3β as an important modulator of miR biogenesis at Microprocessor level. Repression of GSK3β activity reduces Drosha activity toward pri-miRs, leading to accumulation of unprocessed pri-miRs and reduction of pre-miRs and mature miRs without altering levels or cellular localisation of miR biogenesis proteins. Conversely, GSK3β activation increases Drosha activity and mature miR accumulation. GSK3β achieves this through promoting Drosha:cofactor and Drosha:pri-miR interactions: it binds to DGCR8 and p72 in the Microprocessor, an effect dependent upon presence of RNA. Indeed, GSK3β itself can immunoprecipitate pri-miRs, suggesting possible RNA-binding capacity. Kinase assays identify the mechanism for GSK3β-enhanced Drosha activity, which requires GSK3β nuclear localisation, as phosphorylation of Drosha at S300 and/or S302; confirmed by enhanced Drosha activity and association with cofactors, and increased abundance of mature miRs in the presence of phospho-mimic Drosha. Functional implications of GSK3β-enhanced miR biogenesis are illustrated by increased levels of GSK3β-upregulated miR targets following GSK3β inhibition. These data, the first to link GSK3β with the miR cascade in humans, highlight a novel pro-biogenesis role for GSK3β in increasing miR biogenesis as a component of the Microprocessor complex with wide-ranging functional consequences

Mechanisms of jet formation on the giant planets

The giant planet atmospheres exhibit alternating prograde (eastward) and retrograde (westward) jets of different speeds and widths, with an equatorial jet that is prograde on Jupiter and Saturn and retrograde on Uranus and Neptune. The jets are variously thought to be driven by differential radiative heating of the upper atmosphere or by intrinsic heat fluxes emanating from the deep interior. But existing models cannot account for the different flow configurations on the giant planets in an energetically consistent manner. Here a three-dimensional general circulation model is used to show that the different flow configurations can be reproduced by mechanisms universal across the giant planets if differences in their radiative heating and intrinsic heat fluxes are taken into account. Whether the equatorial jet is prograde or retrograde depends on whether the deep intrinsic heat fluxes are strong enough that convection penetrates into the upper troposphere and generates strong equatorial Rossby waves there. Prograde equatorial jets result if convective Rossby wave generation is strong and low-latitude angular momentum flux divergence owing to baroclinic eddies generated off the equator is sufficiently weak (Jupiter and Saturn). Retrograde equatorial jets result if either convective Rossby wave generation is weak or absent (Uranus) or low-latitude angular momentum flux divergence owing to baroclinic eddies is sufficiently strong (Neptune). The different speeds and widths of the off-equatorial jets depend, among other factors, on the differential radiative heating of the atmosphere and the altitude of the jets, which are vertically sheared. The simulations have closed energy and angular momentum balances that are consistent with observations of the giant planets.Comment: 21 pages, 10 figure

Lymph node fibroblastic reticular cells directly present peripheral tissue antigen under steady-state and inflammatory conditions

Lymph node stromal cells (LNSCs) can induce potent, antigen-specific T cell tolerance under steady-state conditions. Although expression of various peripheral tissue–restricted antigens (PTAs) and presentation to naive CD8+ T cells has been demonstrated, the stromal subsets responsible have not been identified. We report that fibroblastic reticular cells (FRCs), which reside in the T cell zone of the LN, ectopically express and directly present a model PTA to naive T cells, inducing their proliferation. However, we found that no single LNSC subset was responsible for PTA expression; rather, each subset had its own characteristic antigen display. Studies to date have concentrated on PTA presentation under steady-state conditions; however, because LNs are frequently inflammatory sites, we assessed whether inflammation altered stromal cell–T cell interactions. Strikingly, FRCs showed reduced stimulation of T cells after Toll-like receptor 3 ligation. We also characterize an LNSC subset expressing the highest levels of autoimmune regulator, which responds potently to bystander inflammation by up-regulating PTA expression. Collectively, these data show that diverse stromal cell types have evolved to constitutively express PTAs, and that exposure to viral products alters the interaction between T cells and LNSCs

Inactivation of SNF5 cooperates with p53 loss to accelerate tumor formation in Snf5 +/− ; p53 +/− mice

Malignant rhabdoid tumors (MRTs) are poorly differentiated pediatric cancers that arise in various anatomical locations and have a very poor outcome. The large majority of these malignancies are caused by loss of function of the SNF5/INI1 component of the SWI/SNF chromatin remodeling complex. However, the mechanism of tumor development associated with SNF5 loss remains unclear. Multiple studies have demonstrated a role for SNF5 in the regulation of cyclin D1, p16INK4A and pRbf activities suggesting it functions through the SWI/SNF complex to affect transcription of genes involved in cell cycle control. Previous studies in genetically engineered mouse models (GEMM) have shown that loss of SNF5 on a p53 null background significantly accelerates tumor development. Here, we use established GEMM to further define the relationship between the SNF5 and p53 tumor suppressor pathways. Combined haploinsufficiency of p53 and Snf5 leads to decreased latency for MRTs arising in alternate anatomical locations but not for the standard facial MRTs. We also observed acceleration in the appearance of T-cell lymphomas in the p53+/-;Snf5+/- mice. Our studies suggest that loss of SNF5 activity does not bestow a selective advantage on the p53 spectrum of tumors in the p53+/-;Snf5+/- mice. However, reduced p53 expression specifically accelerated the growth of a subset of MRTs in these mice

Critical review of strategic planning research in hospitality and tourism

Strategic planning remains one of the most popular management tools, but theoretical and empirical developments in the academic literature have been a slow burn. This paper addresses this gap and provides an up-to-date review of hospitality and tourism strategic planning research. We review strategic planning research from 1995 to 2013 in seven leading tourism academic journals, and adopt a modern and broad conceptualization of strategic planning. While there is some awareness of effective tourism strategic planning processes, academic research has not kept pace with practice. To stimulate a resurgence of research interest, we provide future research directions. We observe a methodological introspection and present some new research methodologies, which are critically important in researching the turbulent, chaotic and nonlinear tourism environment

Optimization of R(e+e-) and "Freezing" of the QCD Couplant at Low Energies

The new result for the third-order QCD corrections to R_{e^+e^-}, unlike the old, incorrect result, is nicely compatible with the principle-of-minimal-sensitivity optimization method. Moreover, it leads to infrared fixed-point behaviour: the optimized couplant, alpha_s/pi, for R(e+e-) does not diverge at low energies, but "freezes" to a value 0.26 below about 300 MeV. This provides some direct theoretical evidence, purely from perturbation theory, for the "freezing" of the couplant -- an idea that has long been a popular and successful phenomenological hypothesis. We use the "smearing" method of Poggio, Quinn, and Weinberg to compare the resulting theoretical prediction for R(e+e-) with experimental data down to the lowest energies, and find excellent agreement.Comment: 27 pages, LaTeX, 8 uuencoded figures, DE-FG05-92ER40717-

A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci.

We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10⁻¹²) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10⁻¹¹) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10⁻⁷) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10⁻¹¹) and a tag SNP for NAT2 acetylation status (P = 4 × 10⁻¹¹), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis

A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci.

We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10⁻¹²) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10⁻¹¹) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10⁻⁷) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10⁻¹¹) and a tag SNP for NAT2 acetylation status (P = 4 × 10⁻¹¹), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis