Cyclin-dependent kinase-mediated phosphorylation of RBP1 and pRb promotes their dissociation to mediate release of the SAP30·mSin3·HDAC transcriptional repressor complex

Eukaryotic cell cycle progression is mediated by phosphorylation of protein substrates by cyclin-dependent kinases (CDKs). A critical substrate of CDKs is the product of the retinoblastoma tumor suppressor gene, pRb, which inhibits G1-S phase cell cycle progression by binding and repressing E2F transcription factors. CDK-mediated phosphorylation of pRb alleviates this inhibitory effect to promote G1-S phase cell cycle progression. pRb represses transcription by binding to the E2F transactivation domain and recruiting the mSin3·histone deacetylase (HDAC) transcriptional repressor complex via the retinoblastoma-binding protein 1 (RBP1). RBP1 binds to the pocket region of pRb via an LXCXE motif and to the SAP30 subunit of the mSin3·HDAC complex and, thus, acts as a bridging protein in this multisubunit complex. In the present study we identified RBP1 as a novel CDK substrate. RBP1 is phosphorylated by CDK2 on serines 864 and 1007, which are N- and C-terminal to the LXCXE motif, respectively. CDK2-mediated phosphorylation of RBP1 or pRb destabilizes their interaction in vitro, with concurrent phosphorylation of both proteins leading to their dissociation. Consistent with these findings, RBP1 phosphorylation is increased during progression from G 1 into S-phase, with a concurrent decrease in its association with pRb in MCF-7 breast cancer cells. These studies provide new mechanistic insights into CDK-mediated regulation of the pRb tumor suppressor during cell cycle progression, demonstrating that CDK-mediated phosphorylation of both RBP1 and pRb induces their dissociation to mediate release of the mSin3·HDAC transcriptional repressor complex from pRb to alleviate transcriptional repression of E2F.

Investigating the future of project management : a co-word analysis approach

If Project Management (PM) is a well-accepted mode of managing organizations, more and more organizations are adopting PM in order to satisfy the diversified needs of application areas within a variety of industries and organizations. Concurrently, the number of PM practitioners and people involved at various level of qualification is vigorously rising. Thus the importance to characterize, define and understand this field and its underlying strength, basis and development is paramount. For this purpose we will referee to sociology of actor-networks and qualitative scientometrics leading to the choice of the co-word analysis method in enabling us to capture the project management field and its dynamics. Results of a study based on the analysis of EBSCO Business Source Premier Database will be presented and some future trends and scenarios proposed. The main following trends are confirmed, in alignment with previous studies: continuous interest for the “cost engineering” aspects, on going interest for Economic aspects and contracts, how to deal with various project types (categorizations), the integration with Supply Chain Management and Learning and Knowledge Management. Furthermore besides these continuous trends, we can note new areas of interest: the link between strategy and project, Governance, the importance of maturity (organizational performance and metrics, control) and Change Management. We see the actors (Professional Bodies, Governmental Bodies, Agencies, Universities, Industries, Researchers, and Practitioners) reinforcing their competing/cooperative strategies in the development of standards and certifications and moving to more “business oriented” relationships with their members and main stakeholders (Governments, Institutions like European Community, Industries, Agencies, NGOs…), at least at central level.

‘Argue with us!’: audience co-creation through post-performance discussions.

In this article Caroline Heim explores an avenue for the audience's contribution to the theatrical event that has emerged as increasingly important over the past decade: postperformance discussions. With the exception of theatres that actively encourage argument such as the Staatstheater Stuttgart, most extant audience discussions in Western mainstream theatres privilege the voice of the theatre expert. Caroline Heim presents case studies of post-performance discussions held after performances of Anne of the Thousand Days and Who's Afraid of Virginia Woolf? which trialled a new model of audience co-creation. An audience text which informs the theatrical event was created, and a new role, that of audience critic, established in the process.

Co-management to solve homelessness : wicked solutions to wicked problems

While governments are engaged in developing social policy responses to address wicked issues such as poverty, homelessness, drug addiction and crime, long term resolution of these issues through government policy making and state-based programmatic action has remained elusive. The use of vehicles for joint action and partnership between government and the community sector such as co-management has been offered as a way of harnessing productive capability and innovative capacity of both these sectors to resolve these complex problems. However, it is suggested that while there is a well advanced agenda with the intent for collaboration and partnership, working with the models for undertaking this joint action are not well understood and have not been fully developed or evaluated. This chapter examines new approaches to resolving the wicked issue of homelessness through applying the lens of co-management to understand the complexities of this issue and its resolution. The chapter analyses an attempt to move away from traditional bureaucratic structures of welfare departments, operating through single functional ‘silos’ to a new horizontal ‘hub-based’ model of service delivery that seeks to integrate actors across many different service areas and organizations. The chapter explores case studies of co-management in the establishment, development and operation of service hubs to address homelessness. We argue that the response to homelessness needs a ‘wicked solution’ that goes beyond simply providing shelter to those in need. The case of the hub models of community sector organizations working across organizational boundaries is evaluated to determine whether this approach can be considered successful co-managing of an innovative initiative, and understanding the requirements for developing, improving and extending this model. The role of the third sector in co-managing public services is examined through the in-depth case studies and the results are presented together with an assessment of how co-management can contribute to service quality and service management in public services.

Design process excludes users : the co-creation activities between user and designer

User needs are a fundamental element of design. If the design process does not properly reflect user needs, the design will be severely compromised. Therefore, it is worthwhile to investigate how the user is, and user needs are, understood in the design process. In this article, three accepted linear process models for web site and interactive media design are reviewed in terms of the designer and user participation. The article then proposes a user-evolving collaborative design process which is built on co-creation activities between designer and user. Co-creation activities across the entire design process structurally and ontologically reposition the users, and user needs, centrally, which allows the designers to holistically approach to the user needs through building a partnership with the users. Co-creation creates an equal evolving participatory process between user and designer towards sharing values and knowledge and creating new domains of collective creativity.

A parallel cooperative co-evolutionary genetic algorithm for the composite SaaS placement problem in Cloud computing

A composite SaaS (Software as a Service) is a software that is comprised of several software components and data components. The composite SaaS placement problem is to determine where each of the components should be deployed in a cloud computing environment such that the performance of the composite SaaS is optimal. From the computational point of view, the composite SaaS placement problem is a large-scale combinatorial optimization problem. Thus, an Iterative Cooperative Co-evolutionary Genetic Algorithm (ICCGA) was proposed. The ICCGA can find reasonable quality of solutions. However, its computation time is noticeably slow. Aiming at improving the computation time, we propose an unsynchronized Parallel Cooperative Co-evolutionary Genetic Algorithm (PCCGA) in this paper. Experimental results have shown that the PCCGA not only has quicker computation time, but also generates better quality of solutions than the ICCGA.

Alkyl radical geometry controls geminate cage recombination in alkylcobalamins

Abstract: The radical pair that results from photolysis of adenosylcob(II1)alamin (AdoCbl"') undergoes primary geminate recombination with a first-order rate constant of 1 x lo9 s-l. In contrast, methylcob(II1)alamin (CH3Cbl"') and aristeromicylcob(II1)alamin (AriCblII', the carbocyclic analogue of AdoCbl"' in which the ribofuranose ring oxygen has been replaced with a methylene group) does not undergo primary geminate recombination. The ribofwanose group enables a high rate of geminate recombination in the [Ado' Cbl"'] radical pair. This may be due to a stereoelectronic (p-anomeric) effect that maintains a pyramidal geometry at the 5'-carbon of the 5'-deoxyadenosyl radical, or it may be due to hindered rotation about the C4t-C5, bond such that /?-elimination to the olefin is prevented. Recombination in the geminate singlet radical pair is in competition with diffusive escape to form a solvent-separated radical pair. Hyperfine coupling from Co" promotes intersystem crossing to the triplet radical pair (Chagovetz, A. M.; Grissom, C. B. J. Am. Chem. SOC. 1993, 115, 12152). Recombination of the [CH3' Cbl"] radical pair is not prevented by a lack of intersystem crossing, as neither unlabeled or I3C-labeled CH3Cbl"' undergoes geminate recombination. There is only a small difference in the rate of diffusive recombination in the solvent cage for AdoCbl"', AriCbl"', and CH3Cbl"' following photolysis: 2.01 x 10" s-l, 2.20 x lo4 s-l, and 1.16 x lo4 s-l. The rate of diffusive recombination is limited by productive collisions and not by radical geometry or intersystem crossing. The CF3' radical that results from photolysis of (trifluoromethyl)cob(III)alamin (CF3Cbl"') maintains its pyramidal geometry and undergoes faster diffusive recombination in the solvent cage at 51 x lo4 s-l. The C-Co bond dissociation enthalpy in AriCbl"' is 37 f 1.4 kcaymol. The profound difference in geminate recombination rates for AdoCbl"' and CH3Cbl"' is consistent with their different biological roles as enzymatic cofactors: AdoCbl"' is an initiator of radical chain chemistry in the active site, whereas CH3Cbl"' is a methyl group donor in an S~2-type process.

Emergent innovation through the co-evolution of informal and formal media economies

Well-established distinctions between amateur and professional are blurring as the impact of social media, changes in cultural consumption, and crises in copyright industries’ business models are felt across society and economy. I call this the increasingly rapid co-evolution of the formal market and informal household sectors and analyse it through the concept of ‘social network markets’ – individual choices are made on the basis of other’s choices and such networked preferencing is enhanced by the growing ubiquity of social media platforms. This may allow us better to understand sources of disruption and innovation in audiovisual production and distribution in wealthy Western markets which are as significant as those posed by informal practices outside the West. I examine what is happening around the monetization and professionalization of online video (YouTube, for example) and the socialization of professional production strategies (transmedia, for example) as innovation from the margins.

Experimental evidence indicating that mastreviruses probably did not co-diverge with their hosts

Background. Despite the demonstration that geminiviruses, like many other single stranded DNA viruses, are evolving at rates similar to those of RNA viruses, a recent study has suggested that grass-infecting species in the genus Mastrevirus may have co-diverged with their hosts over millions of years. This "co-divergence hypothesis" requires that long-term mastrevirus substitution rates be at least 100,000-fold lower than their basal mutation rates and 10,000-fold lower than their observable short-term substitution rates. The credibility of this hypothesis, therefore, hinges on the testable claim that negative selection during mastrevirus evolution is so potent that it effectively purges 99.999% of all mutations that occur. Results. We have conducted long-term evolution experiments lasting between 6 and 32 years, where we have determined substitution rates of between 2 and 3 × 10 -4substitutions/site/year for the mastreviruses Maize streak virus (MSV) and Sugarcane streak Réunion virus (SSRV). We further show that mutation biases are similar for different geminivirus genera, suggesting that mutational processes that drive high basal mutation rates are conserved across the family. Rather than displaying signs of extremely severe negative selection as implied by the co-divergence hypothesis, our evolution experiments indicate that MSV and SSRV are predominantly evolving under neutral genetic drift. Conclusion. The absence of strong negative selection signals within our evolution experiments and the uniformly high geminivirus substitution rates that we and others have reported suggest that mastreviruses cannot have co-diverged with their hosts. © 2009 Harkins et al; licensee BioMed Central Ltd.

Navigating the muddy waters of the research into single sex classrooms in co-educational middle years settings

Establishing single sex classes within co-educational sites is an option that Australian schools are again exploring. To date Australia has experienced three ‘waves’ of interest in establishing single sex classes, the first focused on equitable education opportunities for girls (Alloway & Gilbert, 1997), the second centered on boys’ literacy and engagement (Gilbert & Gilbert, 1998) and this current wave focuses on perceived difference between the sexes in co-educational classrooms (Protheroe, 2009; Gurian, Stevens & Daniels, 2009). With the intersection of middle schooling movement, focusing on learner centered classrooms (Pendergast & Bahr, 2010) and current educational agendas aimed at improving student performance and measurable learning outcomes (Ministerial Council on Education, Employment, Training and Youth Affairs, 2008), it is understandable that schools are exploring such student grouping options. However, after thirty years of international research into the efficacy of single sex classes in co-educational settings, the results still remain unclear. This paper seeks to navigate the ‘muddy waters’ of this body of research and suggests a framework to help guide school communities through the decision-making process associated with considering single sex classes.