The transcription factor AP-2ɛ regulates CXCL1 during cartilage development and in osteoarthritis

SummaryObjectiveRecently, the transcription factor AP-2ɛ was shown to be a regulator of hypertrophy in cartilage and to be differentially expressed in osteoarthritis (OA). However, the only known target gene of AP-2ɛ up to date is integrin alpha10. To better characterize the function of AP-2ɛ in cartilage we screened for additional target genes.DesignPromoter analysis, ChIP-assays and electrophoretic mobility shift assay were used to characterize the regulation of a new AP-2ɛ target gene in detail.ResultsIn this study, we determined the chemokine CXCL1, already known to be important in osteoarthritis (OA), as a new target gene of AP-2ɛ. We could confirm that CXCL1 is expressed in chondrocytes and significantly over-expressed in OA-chondrocytes. Transient transfection of chondrocytes with an AP-2ɛ expression construct led to a significant increase of the CXCL1 mRNA level in these cells. We identified three potential AP-2 binding sites within the CXCL1 promoter and performed luciferase assays, indicating that an AP-2 binding motif (AP-2.2) ranging from position −135 to −144bp relative to the translation start is responsive to AP-2ɛ. This result was further addressed by site-directed mutagenesis demonstrating that activation of the CXCL1 promoter by AP-2ɛ is exclusively dependent on AP-2.2. Chromatin immunoprecipitation and electromobility shift assays confirmed the direct binding of AP-2ɛ to the CXCL1 promoter in OA-chondrocytes at this site.ConclusionThese findings revealed CXCL1 as a novel target gene of AP-2ɛ in chondrocytes and support the important role of AP-2ɛ in cartilage

Outcomes of a funding initiative to promote allied health research activity: a qualitative realist evaluation

Providing funding for clinicians to have protected time to undertake research can address a commonly cited barrier to research - lack of time. However, limited research has evaluated the impact or mechanisms of such funding initiatives. In the current economic environment, it is important that funding is used efficiently and judiciously and that mechanisms and contexts that may assist with maximising outcomes of funding initiatives are identified. This study aimed to describe the medium-term outcomes of a funding initiative to promote allied health research activity and to identify the key mechanisms and contexts that facilitated these outcomes.We used a qualitative research design informed by a realist evaluation, to conduct 10 semi-structured interviews with allied health professionals who had participated in a funding initiative 1-3 years ago. Questions explored outcomes, mechanisms and contexts of the funding initiative. Data was thematically coded into context-mechanism-outcome configurations.Medium term outcomes included increased individual research opportunities, influence on team research culture and impact on clinical work/practice. Other outcomes included increased clinician confidence, knowledge and skill, and research outputs. However, some participants still had difficulties progressing research. Four context-mechanism-outcome configurations were identified to explain which contexts and mechanisms produced these outcomes. Examples of contexts included perception of managerial support, undertaking a research-based higher degree and joint applications, while mechanisms included accessing infrastructure and resources as well as individual researcher factors like motivation.Providing funding to allied health professionals to undertake and complete research can lead to important outcomes, including increased research opportunities, capacity and culture, increased research outputs, and changes to clinical practice. Outcomes are influenced by unique contexts and mechanisms and these should be considered in future implementation of similar funding initiatives

Beyond osteogenesis: an in vitro comparison of the potentials of six bone morphogenetic proteins

Bone morphogenetic proteins (BMPs) other than the clinically available BMP-2 and BMP-7 may be useful for improving fracture healing through both increasing osteogenesis and creating a favorable healing environment by altering cytokine release by endogenous cells. Given the spectrum of potential applications for BMPs, the objective of this study was to evaluate various BMPs under a variety of conditions to provide further insight into their therapeutic capabilities. The alkaline phosphatase (ALP) activity of both C(2)C(12) and human adipose-derived stem cells (hASCs) was measured after exposure of increasing doses of recombinant human BMP-2, -4, -5, -6, -7, or -9 for 3 and 7 days. BMPs-2, -4, -5, -6, -7, and -9 were compared in terms of their ability to affect the release of stromal derived factor-1 (SDF-1), vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (b-FGF) from human bone marrow stromal cells (hBMSCs). Gene expression of ALP, osteocalcin, SDF-1, VEGF, and b-FGF following shRNA-mediated knockdown of BMP-2 and BMP-6 in hBMSCs or human osteoblasts under osteogenic differentiation conditions was also evaluated. Collectively, BMPs-6 and -9 produced the greatest osteogenic differentiation of C(2)C(12) and hASCs as determined by ALP. The hBMSC secretion of SDF-1 was most affected by BMP-5, VEGF by BMP-4, and b-FGF by BMP-2. The knockdown of BMP-2 in BMSCs had no effect on any of the genes measured whereas BMP-6 knockdown in hBMSCs caused a significant increase in VEGF gene expression. BMP-2 and BMP-6 knockdown in human osteoblasts caused significant increases in VEGF gene expression and trends toward decreases in osteocalcin expression. These findings support efforts to study other BMPs as potential bone graft supplements, and to consider combined BMP delivery for promotion of multiple aspects of fracture healing

Crowdsourcing Cybersecurity: Cyber Attack Detection using Social Media

Social media is often viewed as a sensor into various societal events such as disease outbreaks, protests, and elections. We describe the use of social media as a crowdsourced sensor to gain insight into ongoing cyber-attacks. Our approach detects a broad range of cyber-attacks (e.g., distributed denial of service (DDOS) attacks, data breaches, and account hijacking) in an unsupervised manner using just a limited fixed set of seed event triggers. A new query expansion strategy based on convolutional kernels and dependency parses helps model reporting structure and aids in identifying key event characteristics. Through a large-scale analysis over Twitter, we demonstrate that our approach consistently identifies and encodes events, outperforming existing methods.Comment: 13 single column pages, 5 figures, submitted to KDD 201

Complex problem solving and intelligence: Empirical relation and causal direction

At least two theoretical positions strongly suggest that intelligence and problem solving are related. First, the ability to solve problems features prominent in almost every definition of human “intelligence;” thus, problem-solving capacity is viewed as one component of intelligence. Second, intelligence is often assumed to be a predictor of problem-solving ability. Our main goal in this chapter is to review to what extent the ability to solve complex, rather than simple laboratory, problems is indeed tied, empirically, to intelligence, and, which causal direction holds between the two concepts. The chapter is divided into three main sections. In the first section, we provide a definition of “complex problem solving.” In the second and third sections, we review much of the existing empirical work that relates complex problem-solving competence to intelligence. We distinguish two forms of complex problem solving. In the second section, we focus on explicit problem solving, that is, on problem solving that is controlled by a problem solver’s intentions. In the third section our focus is on implicit, that is, on automatic or non-conscious complex problem solving. Our main conclusions are that, first, there exists little, if any, empirical evidence that supports a relation between explicit complex problem-solving and global intelligence. Second, there is also no empirical evidence indicating that global intelligence and implicit complex problem solving might be related. Third, however, there exists a considerable amount of empirical data suggesting that specific components of intelligence, such as processing capacity, might be related to specific components of explicit complex problem solving. Together, the available evidence suggests that the global concepts of intelligence and problem solving are not related, but that specific subcomponents of intelligence and explicit problem solving might share variance. The existing empirical evidence does not speak, however, to the issue of whether subcomponents of intelligence predict subcomponents of problem solving or whether the opposite causal relation holds

Foresight-Studie "Digitale Arbeitswelt"

Die Foresight-Studie "Digitale Arbeitswelt" des Instituts für Innovation und Technik (iit) im Auftrag des BMAS stellt die möglichen Entwicklungen der Arbeitswelt in den Branchen Produktion, Medien und Dienstleistungen in einer mittel- und langfristigen Perspektive dar. Die Studie geht dabei auf neue Formen der Automatisierung, der innerbetrieblichen Arbeitsorganisation sowie neue digital vermittelte Formen der Arbeitsteilung ein. Zentrales Ergebnis sind drei Roadmaps zur möglichen Entwicklung der einzelnen Branchen sowie branchenübergreifende Thesen zu Veränderungen der Arbeitswelt durch die Digitalisierung

Geologically constrained evolutionary geomechanical modelling of diapir and basin evolution: a case study from the Tarfaya basin, West African coast

We systematically incorporate burial history, sea floor geometry and tectonic loads from a sequential kinematic restoration model into a 2D evolutionary geomechanical model that simulates the formation of the Sandia salt diapir, Tarfaya basin, NW African Coast. We use a poro-elastoplastic description for the sediment behaviour and a viscoplastic description for the salt. Sedimentation is coupled with salt flow and regional shortening to determine the sediment porosity and strength and to capture the interaction between salt and sediments. We find that temporal and spatial variation in sedimentation rate is a key control on the kinematic evolution of the salt system. Incorporation of sedimentation rates from the kinematic restoration at a location east of Sandia leads to a final geomechanical model geometry very similar to that observed in seismic reflection data. We also find that changes in the variation of shortening rates can significantly affect the present-day stress state above salt. Overall, incorporating kinematic restoration data into evolutionary models provides insights into the key parameters that control the evolution of geologic systems. Furthermore, it enables more realistic evolutionary geomechanical models, which, in turn, provide insights into sediment stress and porosity

Characterization of THB1, a Chlamydomonas reinhardtii truncated hemoglobin: linkage to nitrogen metabolism and identification of lysine as the distal heme ligand

The nuclear genome of the model organism Chlamydomonas reinhardtii contains genes for a dozen hemoglobins of the truncated lineage. Of those, THB1 is known to be expressed, but the product and its function have not yet been characterized. We present mutagenesis, optical, and nuclear magnetic resonance data for the recombinant protein and show that at pH near neutral in the absence of added ligand, THB1 coordinates the heme iron with the canonical proximal histidine and a distal lysine. In the cyanomet state, THB1 is structurally similar to other known truncated hemoglobins, particularly the heme domain of Chlamydomonas eugametos LI637, a light-induced chloroplastic hemoglobin. Recombinant THB1 is capable of binding nitric oxide (NO(*)) in either the ferric or ferrous state and has efficient NO(*) dioxygenase activity. By using different C. reinhardtii strains and growth conditions, we demonstrate that the expression of THB1 is under the control of the NIT2 regulatory gene and that the hemoglobin is linked to the nitrogen assimilation pathway