Regulation of Adipocyte Transcription by PPARgamma Ligands

Rosiglitazone (rosi) is a powerful insulin sensitizer, but serious toxicities have curtailed its widespread clinical use. Rosi functions as a high-affinity ligand for PPARgamma, the adipocyte-predominant nuclear receptor (NR). The classic model of NR action, involving binding of ligand to the NR on DNA, explains positive regulation of gene expression, but both ligand-dependent transcriptional repression and indirect regulation are not well understood. We have addressed these issues by studying the direct effects of rosiglitazone on gene transcription, using global run-on sequencing (GRO-seq). Rosi-induced changes in gene body transcription were pronounced after 10 minutes and correlated with steady-state mRNA levels as well as with transcription at nearby enhancers (eRNAs). Up-regulated eRNAs occurred almost exclusively at PPARg binding sites, to which rosi treatment recruited coactivators including MED1, p300, and CBP, without changes in binding of the corepressor NCoR. By contrast, down-regulated eRNAs fell in sites devoid of PPARg but enriched for a variety of other TFs in the C/EBP and AP-1 families. These enhancers lost coactivator binding upon rosi treatment, suggesting that rosi treatment causes redistribution of coactivators to PPARg sites and away from enhancers containing other TFs, leading to transcriptional repression at these eRNAs and their target genes. We also investigated the function of MRL-24, a compound that has been shown to lack PPARg transactivation activity and regulate a distinct subset of PPARg target genes while functioning as an equally effective insulin sensitizer as rosi. Though our goal was to identify whether MRL-24 regulates the same functional enhancers marked by eRNAs as rosi, we instead found that MRL-24 does not control a distinct subset of target genes, but rather acts as a partial agonist for PPARg. Together, these studies further our understanding of transcriptional regulation by modulation of PPARg activity, including insights into determining functional enhancers and mechanisms of transcriptional repression by activation of a NR

Dynamic Quality of Service in Software-Defined Networks

Quality of service is a necessary function of today’s networks. A proper quality of service ensures that packets are delivered effectively and fast. In traditional networks, quality of service has to be manually configured on each piece of hardware in the network. This manual procedure makes the process of implementing a quality of service in a network costly. Not to mention, if part of the configuration is incorrect, or a mistake is made during the configuration, everything must be corrected on each piece of affected hardware. In this paper, I will be exploring the effect of using a software-defined network controller and a quality of service to handle certain flows of traffic in a network. The main tool used is the OpenFlow defined queue. Queues and flow rules will allow a switch to control individual flows and the network resources that each flow consumes. Factors that will be explored are the bandwidth usage of a flow and the time taken by the network to implement new flow rules. While bandwidth usage is taken into account in traditional networks, changing a quality of service is a new dynamic

A step too far? Leader racism inhibits transgression credit

Prior research established that when in-group leaders commit serious transgressions, such as breaking enforceable rules or engaging in bribery, people treat them leniently compared with similarly transgressive regular group members or out-group leaders (‘transgression credit’). The present studies test a boundary condition of this phenomenon, specifically the hypothesis that transgression credit will be lost if a leader's action implies racist motivation. In study 1, in a corporate scenario, a transgressive in-group leader did or did not express racism. In study 2, in a sports scenario, an in-group or out-group leader or member transgressed rules with or without a racist connotation. Both studies showed that in-group transgressive leaders lost their transgression credit if their transgression included a racial connotation. Wider implications for constraining leaders' transgressions are discussed

A safer place for patients: learning to improve patient safety

1 Every day over one million people are treated successfully by National Health Service (NHS) acute, ambulance and mental health trusts. However, healthcare relies on a range of complex interactions of people, skills, technologies and drugs, and sometimes things do go wrong. For most countries, patient safety is now the key issue in healthcare quality and risk management. The Department of Health (the Department) estimates that one in ten patients admitted to NHS hospitals will be unintentionally harmed, a rate similar to other developed countries. Around 50 per cent of these patient safety incidentsa could have been avoided, if only lessons from previous incidents had been learned. 2 There are numerous stakeholders with a role in keeping patients safe in the NHS, many of whom require trusts to report details of patient safety incidents and near misses to them (Figure 2). However, a number of previous National Audit Office reports have highlighted concerns that the NHS has limited information on the extent and impact of clinical and non-clinical incidents and trusts need to learn from these incidents and share good practice across the NHS more effectively (Appendix 1). 3 In 2000, the Chief Medical Officer’s report An organisation with a memory 1 , identified that the key barriers to reducing the number of patient safety incidents were an organisational culture that inhibited reporting and the lack of a cohesive national system for identifying and sharing lessons learnt. 4 In response, the Department published Building a safer NHS for patients3 detailing plans and a timetable for promoting patient safety. The goal was to encourage improvements in reporting and learning through the development of a new mandatory national reporting scheme for patient safety incidents and near misses. Central to the plan was establishing the National Patient Safety Agency to improve patient safety by reducing the risk of harm through error. The National Patient Safety Agency was expected to: collect and analyse information; assimilate other safety-related information from a variety of existing reporting systems; learn lessons and produce solutions. 5 We therefore examined whether the NHS has been successful in improving the patient safety culture, encouraging reporting and learning from patient safety incidents. Key parts of our approach were a census of 267 NHS acute, ambulance and mental health trusts in Autumn 2004, followed by a re-survey in August 2005 and an omnibus survey of patients (Appendix 2). We also reviewed practices in other industries (Appendix 3) and international healthcare systems (Appendix 4), and the National Patient Safety Agency’s progress in developing its National Reporting and Learning System (Appendix 5) and other related activities (Appendix 6). 6 An organisation with a memory1 was an important milestone in the NHS’s patient safety agenda and marked the drive to improve reporting and learning. At the local level the vast majority of trusts have developed a predominantly open and fair reporting culture but with pockets of blame and scope to improve their strategies for sharing good practice. Indeed in our re-survey we found that local performance had continued to improve with more trusts reporting having an open and fair reporting culture, more trusts with open reporting systems and improvements in perceptions of the levels of under-reporting. At the national level, progress on developing the national reporting system for learning has been slower than set out in the Department’s strategy of 2001 3 and there is a need to improve evaluation and sharing of lessons and solutions by all organisations with a stake in patient safety. There is also no clear system for monitoring that lessons are learned at the local level. Specifically: a The safety culture within trusts is improving, driven largely by the Department’s clinical governance initiative 4 and the development of more effective risk management systems in response to incentives under initiatives such as the NHS Litigation Authority’s Clinical Negligence Scheme for Trusts (Appendix 7). However, trusts are still predominantly reactive in their response to patient safety issues and parts of some organisations still operate a blame culture. b All trusts have established effective reporting systems at the local level, although under-reporting remains a problem within some groups of staff, types of incidents and near misses. The National Patient Safety Agency did not develop and roll out the National Reporting and Learning System by December 2002 as originally envisaged. All trusts were linked to the system by 31 December 2004. By August 2005, at least 35 trusts still had not submitted any data to the National Reporting and Learning System. c Most trusts pointed to specific improvements derived from lessons learnt from their local incident reporting systems, but these are still not widely promulgated, either within or between trusts. The National Patient Safety Agency has provided only limited feedback to trusts of evidence-based solutions or actions derived from the national reporting system. It published its first feedback report from the Patient Safety Observatory in July 2005

Step forward in Grammar

Навчально-методичний посібник призначено для студентів і аспірантів немовних факультетів університету. У посібнику подано теоретичний та практичний матеріал з граматики англійської мови. Метою посібника є розвиток умінь раціонально опрацьовувати спеціалізовані англомовні тексти. Структура посібника дозволяє обрати оптимальні способи організації роботи для ефективного засвоєння матеріалу та аналітичної обробки інформації

Second consultation on developing standards for identifying evidence-based practices in reproductive health

The STEP UP consortium and the High Impact Practices initiative, together with other partners, supported three consultation meetings to inform the use of appropriate standards of evidence for recommending best practices in reproductive health (RH). The second consultation, reported here, brought together researchers and funders to review the research designs and methodologies that can be used to generate evidence on the impact of FP/RH interventions and on their implementation; the mechanisms and structures through which such evidence is reviewed and translated into recommendations; and the implications for organizing and funding evidence generation to maximize its quality and utility. Drawing from the presentations, three plenary discussions were held which reflected a diversity of views on what constitutes high-quality evidence, which type of evidence is appropriate for which type of recommendations, and which approaches should be followed to translate evidence into practice recommendations. Recommendations for consolidating standards of evidence and formulating guidelines for high-impact practices in FP/RH programming and policymaking are presented in this report

Multicanonical Simulations Step by Step

The purpose of this article is to provide a starter kit for multicanonical simulations in statistical physics. Fortran code for the $q$-state Potts model in $d=2, 3,...$ dimensions can be downloaded from the Web and this paper describes simulation results, which are in all details reproducible by running prepared programs. To allow for comparison with exact results, the internal energy, the specific heat, the free energy and the entropy are calculated for the $d=2$ Ising ($q=2$) and the $q=10$ Potts model. % in a temperature range from $T=\infty$ down to sufficiently low % temperatures, such that the groundstates are included in the sampling. Analysis programs, relying on an all-log jackknife technique, which is suitable for handling sums of very large numbers, are introduced to calculate our final estimators

Step-By-Step Strategic Consulting

abstract: Step-By-Step Strategic Consulting is the professional consulting organization being created by Tanya Rincon and Kindra Maples in Phoenix, Arizona. Taking the initial steps into entrepreneurship is difficult without a guide or professional network to lean on and Step-By-Step plans to be there to make it more attainable. This organization functions with sustainable business practices as the foundation of every decision that is made. Beyond the assumed assistance that comes with partnering with a consulting service, Step-By-Step is dedicated to developing and fostering a network of values aligned startups and entrepreneurs that are prepared to support one another. The classic approach to capitalism has created incredible innovation for our world as a whole but it has also created massive issues for our environment and the communities that each organization serves. Sustainability issues are pervasive in every community, ecosystem, and economy yielding complex worldwide problems. As the business world shifts to supporting a new generation, it’s important to build resilient organizations prepared for the dynamic landscape that is currently forming. While the profession of business consulting and startup accelerators is not new, a new type of strategic business thinker is coming to be in the form of sustainable business practices. Step-By-Step Strategic Consulting aims to provide an additional option in the strategic consulting world, with sustainability at the center. Additionally, a roadmap has been created to provide a clear plan for future investors, clients, and employees. This plan includes a specific timeline detailing necessary steps to become a legitimate business legally, development plans for each business partner, and steps necessary for securing funding and strategic investors. Graduate Culminating Experience Sharing Permissions Agreement Mission: Step-By-Step guides and supports startup clients through the various stages of strategic growth with sustainable business practices as the foundation of success to create a positive impact environmentally, socially, and financially. Vision: A collaborative network of values aligned organizations working together to accomplish their individual goals, while also supporting the success of the United Nations Sustainable Development Goals