14-3-3ζ Interacts with Stat3 and Regulates Its Constitutive Activation in Multiple Myeloma Cells

The 14-3-3 proteins are a family of regulatory signaling molecules that interact with other proteins in a phosphorylation-dependent manner and function as adapter or scaffold proteins in signal transduction pathways. One family member, 14-3-3ζ, is believed to function in cell signaling, cycle control, and apoptotic death. A systematic proteomic analysis done in our laboratory has identified signal transducers and activators of transcription 3 (Stat3) as a novel 14-3-3ζ interacting protein. Following our initial finding, in this study, we provide evidence that 14-3-3ζ interacts physically with Stat3. We further demonstrate that phosphorylation of Stat3 at Ser727 is vital for 14-3-3ζ interaction and mutation of Ser727 to Alanine abolished 14-3-3ζ/Stat3 association. Inhibition of 14-3-3ζ protein expression in U266 cells inhibited Stat3 Ser727 phosphorylation and nuclear translocation, and decreased both Stat3 DNA binding and transcriptional activity. Moreover, 14-3-3ζ is involved in the regulation of protein kinase C (PKC) activity and 14-3-3ζ binding to Stat3 protects Ser727 dephosphorylation from protein phosphatase 2A (PP2A). Taken together, our findings support the model that multiple signaling events impinge on Stat3 and that 14-3-3ζ serves as an essential coordinator for different pathways to regulate Stat3 activation and function in MM cells

Methods for specifying the target difference in a randomised controlled trial : the Difference ELicitation in TriAls (DELTA) systematic review

Peer reviewedPublisher PD

Integration of P2Y receptor-activated signal transduction pathways in G protein-dependent signalling networks

The role of nucleotides in intracellular energy provision and nucleic acid synthesis has been known for a long time. In the past decade, evidence has been presented that, in addition to these functions, nucleotides are also autocrine and paracrine messenger molecules that initiate and regulate a large number of biological processes. The actions of extracellular nucleotides are mediated by ionotropic P2X and metabotropic P2Y receptors, while hydrolysis by ecto-enzymes modulates the initial signal. An increasing number of studies have been performed to obtain information on the signal transduction pathways activated by nucleotide receptors. The development of specific and stable purinergic receptor agonists and antagonists with therapeutical potential largely contributed to the identification of receptors responsible for nucleotide-activated pathways. This article reviews the signal transduction pathways activated by P2Y receptors, the involved second messenger systems, GTPases and protein kinases, as well as recent findings concerning P2Y receptor signalling in C6 glioma cells. Besides vertical signal transduction, lateral cross-talks with pathways activated by other G protein-coupled receptors and growth factor receptors are discussed

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

Evaluation and Management of Nonculprit Lesions in STEMI

Nonculprit lesions are frequently observed in patients with ST-segment elevation myocardial infarction. Results from recent randomized clinical trials suggest that complete revascularization after ST-segment elevation myocardial infarction improves outcomes. In this state-of-the-art paper, the authors review these trials and consider how best to determine which nonculprit lesions require revascularization and when this should be performed.info:eu-repo/semantics/publishedVersio

Neuroinflammation in cognitive decline post-cardiac surgery (the FOCUS study): an observational study protocol

Introduction Postoperative cognitive dysfunction occurs frequently after coronary artery bypass grafting (CABG). The underlying mechanisms remain poorly understood, but neuroinflammation might play a pivotal role. We hypothesise that systemic inflammation induced by the surgical trauma could activate the innate immune (glial) cells of the brain. This could lead to an exaggerated neuroinflammatory cascade, resulting in neuronal dysfunction and loss of neuronal cells. Therefore, the aims of this study are to assess neuroinflammation in vivo presurgery and postsurgery in patients undergoing major cardiac surgery and investigate whether there is a relationship of neuroinflammation to cognitive outcomes, changes to brain structure and function, and systemic inflammation.Methods and analysis The FOCUS study is a prospective, single-centre observational study, including 30 patients undergoing elective on-pump CABG. Translocator protein (TSPO) positron emission tomography neuroimaging will be performed preoperatively and postoperatively using the second generation tracer 18F-DPA-714 to assess the neuroinflammatory response. In addition, a comprehensive cerebral MRI will be performed presurgery and postsurgery, in order to discover newly developed brain and vascular wall lesions. Up to 6 months postoperatively, serial extensive neurocognitive assessments will be performed and blood will be obtained to quantify systemic inflammatory responses and peripheral immune cell activation.Ethics and dissemination Patients do not benefit directly from engaging in the study, but imaging neuroinflammation is considered safe and no side effects are expected. The study protocol obtained ethical approval by the Medical Research Ethics Committee region Arnhem-Nijmegen. This work will be published in peer-reviewed international medical journals and presented at medical conferences.Trial registration number NCT04520802

A control benchmark on the energy management of a plug-in hybrid electric vehicle

A benchmark control problem was developed for a special session of the IFAC Workshop on Engine and Powertrain Control, Simulation and Modeling (E-COSM 12), held in Rueil-Malmaison, France, in October 2012. The online energy management of a plug-in hybrid-electric vehicle was to be developed by the benchmark participants. The simulator, provided by the benchmark organizers, implements a model of the GM Voltec powertrain. Each solution was evaluated according to several metrics, comprising of energy and fuel economy on two driving profiles unknown to the participants, acceleration and braking performance, computational performance. The nine solutions received are analyzed in terms of the control technique adopted (heuristic rule-based energy management vs. equivalent consumption minimization strategies, ECMS), battery discharge strategy (charge depleting–charge sustaining vs. blended mode), ECMS implementation (vector-based vs. map-based), ways to improve the implementation and improve the computational performance. The solution having achieved the best combined score is compared with a global optimal solution calculated offline using the Pontryagin's minimum principle-derived optimization tool HOT

Looking Into the New ASAS Classification Criteria for Axial Spondyloarthritis Through the Other Side of the Glass

© 2015, Springer Science+Business Media New York.The new concept of axial spondylitis (axSpA) and the Assessment of Spondyloarthritis International Society (ASAS) classification criteria for axSpA have induced new clinical research that has broadened our understanding of spondyloarthritis (SpA) and has had indeed a positive impact on earlier diagnosis and treatment of patients with axSpA who have not yet developed radiographic sacroiliitis. The primary goal of any valid classification criteria for any disease is to provide a homogeneous study population with a common etiopathogenesis, similar prognosis, and similar response to identical treatment. Without such a homogeneous study population, robust clinical and basic science research in any subtype of SpA is not possible. All criteria are dynamic concepts that need updating as our knowledge advances and our review of the ASAS classification criteria of axSpA indicates that complex multi-selection design and unclear (not mutually exclusive) definitions of the imaging and clinical arms of the criteria results in patient heterogeneity across study populations. Therefore, there is a need to improve the validity of the ASAS criteria for axSpA. It is our opinion that in the meantime, the clinically well-established entity of AS, as defined by the modified New York (mNY) criteria, should be preserved for the most accurate comparison of the new research studies with those conducted over the last three decades, and that the use of the ASAS criteria should be restricted to patients with nr-axSpA, who are not recognized by the mNY criteria