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

Cost-based Modeling for Fraud and Intrusion Detection: Results from the JAM Project

We describe the results achieved using the JAM distributed data mining system for the real world problem of fraud detection in financial information systems. For this domain we provide clear evidence that state-of-the-art commercial fraud detection systems can be substantially improved in stopping losses due to fraud by combining multiple models of fraudulent transaction shared among banks. We demonstrate that the traditional statistical metrics used to train and evaluate the performance of learning systems (i.e. statistical accuracy or ROC analysis) are misleading and perhaps inappropriate for this application. Cost-based metrics are more relevant in certain domains, and defining such metrics poses significant and interesting research questions both in evaluating systems and alternative models, and in formalizing the problems to which one may wish to apply data mining technologies. This paper also demonstrates how the techniques developed for fraud detection can be generalized and applied to the important area of intrusion detection in networked information systems. We report the outcome of recent evaluations of our system applied to tcpdump network intrusion data specifically with respect to statistical accuracy. This work involved building additional components of JAM that we have come to call, MADAM ID (Mining Audit Data for Automated Models for Intrusion Detection). However, taking the next step to define cost-based models for intrusion detection poses interesting new research questions. We describe our initial ideas about how to evaluate intrusion detection systems using cost models learned during our work on fraud detection

A German translation and validation of the sense of agency scale

Sense of agency refers to the experience of controlling one’s actions and through them events in the outside world. General agency beliefs can be measured with the Sense of Agency Scale (SoAS), which consists of the sense of positive agency subscale (i.e., feeling of being in control over one’s own body, mind, and environment) and the sense of negative agency subscale (i.e., feeling existentially helpless). The aim of the present study was to validate a German version of the SoAS. Using factor analyzes, we replicated the two-factor structure of the original version of the SoAS. Further, the German SoAS showed good model fits, good internal consistency, and moderate test–retest reliability. Construct validity was supported by significant low to moderate correlations of the German SoAS with other conceptually similar, but still distinct constructs such as general self-efficacy. Additionally, the German SoAS has an incremental value in explaining variance in the extent of subclinical symptoms of schizotypal personality disorder that goes beyond variance explained by constructs that are conceptually similar to sense of agency. Taken together, the results indicate that the German SoAS is a valid and suitable instrument to assess one’s general agency beliefs

Severe muscle trauma triggers heightened and prolonged local musculoskeletal inflammation and impairs adjacent tibia fracture healing

Objectives: Complicated fracture healing is often associated with the severity of surrounding muscle tissue trauma. Since inflammation is a primary determinant of musculoskeletal health and regeneration, it is plausible that delayed healing and non-unions are partly caused by compounding local inflammation in response to concomitant muscle trauma. Methods and results: To investigate this possibility, a Lewis rat open fracture model [tibia osteotomy with adjacent tibialis anterior (TA) muscle volumetric muscle loss (VML) injury] was interrogated. We observed that VML injury impaired tibia healing, as indicated by diminished mechanical strength and decreased mineralized bone within the fracture callus, as well as continued presence of cartilage instead of woven bone 28 days post-injury. The VML injured muscle presented innate and adaptive immune responses that were atypical of canonical muscle injury healing. Additionally, the VML injury resulted in a perturbation of the inflammatory phase of fracture healing, as indicated by elevations of CD3+ lymphocytes and CD68+ macrophages in the fracture callus at 3 and 14d post-injury, respectively. Conclusions: These data indicate that heightened and sustained innate and adaptive immune responses to traumatized muscle are associated with impaired fracture healing and may be targeted for the prevention of delayed and non-union following musculoskeletal trauma

It Was Me: The Use of Sense of Agency Cues Differs Between Cultures

Sense of agency (SoA) is the sense of having control over one’s own actions and through them events in the outside world. SoA may be estimated by integrating different agency cues. In the present study, we examined whether the use of different agency cues – action-effect congruency, temporal relation between action and effect, and affective valence of effects – differs between Eastern (Mongolian) and Western (Austrian) cultures. In a learning phase, participants learned to associate different actions (keypresses) with positive and negative action effects (smileys). In a test phase, participants performed the same keypresses. After different intervals positive and negative action effects, which were either congruent or incongruent with the previously acquired action-effect associations, were presented. In each trial participants were asked to rate how likely the action effect was caused by themselves or by the computer (authorship ratings). In both groups authorship ratings were higher for congruent compared to incongruent action effects and for positive compared to negative action effects. This indicates that action-effect congruency and affective valence of action effects modulate SoA. Further, in both groups the difference between positive and negative effects was higher with congruent effects than incongruent effects. This overadditive effect of action-effect congruency and affective valence might indicate that an integration of different agency cues takes place. Decreasing authorship ratings with increasing interval were observed in Austrians but not in Mongolians. For Mongolians, the temporal chronology of events might be less important when inferring causality. Therefore, information regarding the temporal occurrence of the effect might not be used as an agency cue in Mongolians. In conclusion, some agency cues might be similarly used in different cultures, but the use of others might be culture-dependent

Insights from Amphioxus into the Evolution of Vertebrate Cartilage

Central to the story of vertebrate evolution is the origin of the vertebrate head, a problem difficult to approach using paleontology and comparative morphology due to a lack of unambiguous intermediate forms. Embryologically, much of the vertebrate head is derived from two ectodermal tissues, the neural crest and cranial placodes. Recent work in protochordates suggests the first chordates possessed migratory neural tube cells with some features of neural crest cells. However, it is unclear how and when these cells acquired the ability to form cellular cartilage, a cell type unique to vertebrates. It has been variously proposed that the neural crest acquired chondrogenic ability by recruiting proto-chondrogenic gene programs deployed in the neural tube, pharynx, and notochord. To test these hypotheses we examined the expression of 11 amphioxus orthologs of genes involved in neural crest chondrogenesis. Consistent with cellular cartilage as a vertebrate novelty, we find that no single amphioxus tissue co-expresses all or most of these genes. However, most are variously co-expressed in mesodermal derivatives. Our results suggest that neural crest-derived cartilage evolved by serial cooption of genes which functioned primitively in mesoderm

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

Differential Dynamics of Transposable Elements during Long-Term Diploidization of Nicotiana Section Repandae (Solanaceae) Allopolyploid Genomes

PubMed ID: 23185607This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Carbon stable isotope analysis of cereal remains as a way to reconstruct water availability: preliminary results

Reconstructing past water availability, both as rainfall and irrigation, is important to answer questions about the way society reacts to climate and its changes and the role of irrigation in the development of social complexity. Carbon stable isotope analysis of archaeobotanical remains is a potentially valuable method for reconstructing water availability. To further define the relationship between water availability and plant carbon isotope composition and to set up baseline values for the Southern Levant, grains of experimentally grown barley and sorghum were studied. The cereal crops were grown at three stations under five different irrigation regimes in Jordan. Results indicate that a positive but weak relationship exists between irrigation regime and total water input of barley grains, but no relationship was found for sorghum. The relationship for barley is site-specific and inter-annual variation was present at Deir ‘Alla, but not at Ramtha and Khirbet as-Samra

Human gestational N‐methyl‐d‐aspartate receptor autoantibodies impair neonatal murine brain function

Objective: Maternal autoantibodies are a risk factor for impaired brain development in offspring. Antibodies (ABs) against the NR1 (GluN1) subunit of the N-methyl-d-aspartate receptor (NMDAR) are among the most frequently diagnosed anti-neuronal surface ABs, yet little is known about effects on fetal development during pregnancy. Methods: We established a murine model of in utero exposure to human recombinant NR1 and isotype-matched nonreactive control ABs. Pregnant C57BL/6J mice were intraperitoneally injected on embryonic days 13 and 17 each with 240μg of human monoclonal ABs. Offspring were investigated for acute and chronic effects on NMDAR function, brain development, and behavior. Results: Transferred NR1 ABs enriched in the fetus and bound to synaptic structures in the fetal brain. Density of NMDAR was considerably reduced (up to -49.2%) and electrophysiological properties were altered, reflected by decreased amplitudes of spontaneous excitatory postsynaptic currents in young neonates (-34.4%). NR1 AB-treated animals displayed increased early postnatal mortality (+27.2%), impaired neurodevelopmental reflexes, altered blood pH, and reduced bodyweight. During adolescence and adulthood, animals showed hyperactivity (+27.8% median activity over 14 days), lower anxiety, and impaired sensorimotor gating. NR1 ABs caused long-lasting neuropathological effects also in aged mice (10 months), such as reduced volumes of cerebellum, midbrain, and brainstem. Interpretation: The data collectively support a model in which asymptomatic mothers can harbor low-level pathogenic human NR1 ABs that are diaplacentally transferred, causing neurotoxic effects on neonatal development. Thus, AB-mediated network changes may represent a potentially treatable neurodevelopmental congenital brain disorder contributing to lifelong neuropsychiatric morbidity in affected children