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Hou, Bin, Hiroaki Ogata, Masayuki Miyata, Mengmeng Li, and Yuqin Liu. "JAMIOLAS 3.0." International Journal of Mobile and Blended Learning 2, no. 1 (January 2010): 40–54. http://dx.doi.org/10.4018/jmbl.2010010103.
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In this article, the authors propose an improved context-aware system to support the learning of Japanese mimicry and onomatopoeia (MIO) using sensor data. In the authors’ two previous studies, they proposed a context-aware language learning assistant system named JAMIOLAS (JApanese MImicry and Onomatopoeia Learning Assistant System). The authors used wearable sensors and sensor networks, respectively, to support learning Japanese MIO. To address the disadvantages of the previous systems, the authors propose a new learning model that can support learning MIO, using sensor data and the sensor network to enable context-aware learning by either initiating the creation of context or detecting context automatically.
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Hutchins, Susan G., Alex Bordetsky, Tony Kendall, and Maura Garrity. "Evaluating a Model of Team Collaboration via Analysis of Team Communications." Proceedings of the Human Factors and Ergonomics Society Annual Meeting 51, no. 4 (October 2007): 415–19. http://dx.doi.org/10.1177/154193120705100456.
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A model of team collaboration was developed that emphasizes the macro-cognitive processes entailed in collaboration and includes major processes that underlie this type of communication: (1) individual knowledge building, (2) developing knowledge inter-operability, (3) team shared understanding, and (4) developing team consensus. This paper describes research conducted to empirically validate this model. Team communications that transpired during two complex problem solving situations were coded using cognitive process definitions included in the model. Data was analyzed for three teams that conducted a Maritime Interdiction Operation (MIO) and four teams that engaged in air-warfare scenarios. MIO scenarios involve a boarding team that boards a suspect ship to search for contraband cargo (e.g. explosives, machinery) and possible terrorist suspects. Air-warfare scenarios involve identifying air contacts in the combat information center of an Aegis ship. The way the teams' behavior on the two scenarios maps to the model of team collaboration is discussed.
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Babst, Flurin, Olivier Bouriaud, Benjamin Poulter, Valerie Trouet, Martin P. Girardin, and David C. Frank. "Twentieth century redistribution in climatic drivers of global tree growth." Science Advances 5, no. 1 (January 2019): eaat4313. http://dx.doi.org/10.1126/sciadv.aat4313.
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Energy and water limitations of tree growth remain insufficiently understood at large spatiotemporal scales, hindering model representation of interannual or longer-term ecosystem processes. By assessing and statistically scaling the climatic drivers from 2710 tree-ring sites, we identified the boreal and temperate land areas where tree growth during 1930–1960 CE responded positively to temperature (20.8 ± 3.7 Mio km2; 25.9 ± 4.6%), precipitation (77.5 ± 3.3 Mio km2; 96.4 ± 4.1%), and other parameters. The spatial manifestation of this climate response is determined by latitudinal and altitudinal temperature gradients, indicating that warming leads to geographic shifts in growth limitations. We observed a significant (P< 0.001) decrease in temperature response at cold-dry sites between 1930–1960 and 1960–1990 CE, and the total temperature-limited area shrunk by −8.7 ± 0.6 Mio km2. Simultaneously, trees became more limited by atmospheric water demand almost worldwide. These changes occurred under mild warming, and we expect that continued climate change will trigger a major redistribution in growth responses to climate.
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Rusdiana, I. Wayan, Dyan Primana Sobarudin, M. Qisthi Amarona, and A. Lufti Ibrahim. "Studi Kartografi Marine Protected Area (MPA) di Pulau Sangiang Menggunakan Model Marine Information Overlay (MIO)." Jurnal Chart Datum 5, no. 1 (July 9, 2020): 45–70. http://dx.doi.org/10.37875/chartdatum.v5i1.146.
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MIO merupakan informasi non-wajib yang belum tercakup oleh IMO yang ada, IHO, atau IEC standar yang diperlukan oleh ECDIS untuk memastikan keamanan navigasi di laut. Informasi tambahan ini meliputi peliputan es, pasang / ketinggian air, aliran arus, habitat meteorologi, oseanografi dan laut. Area Konservasi yang juga dikenal dengan istilah MPA merupakan bagian dari MIO yang berguna untuk melindungi spesies ikan, habitat langka, atau seluruh ekosistem di laut. ENC sebagai alat navigasi wajib bagi para pelaut sudah mengakomodir unsur-unsur yang terkait dengan area konservasi, namun belum menyediakan informasi secara detail tipe dan jenis area konservasi tersebut. Pada penelitian ini, MPA yang merupakan bagian dari MIO yang nantinya akan dikembangkan sebagai Special publication S-122 MPA akan dibuat zonasi dengan informasi maupun batasan-batasan secara jelas dan detail dengan cara menerjemahkan dan menganalisa peraturan maupun perundang-undangan yang berlaku di Indonesia ke dalam bahasa peta selanjutnya disesuaikan sesuai dengan dengan standar internasional S-122 MPA sehingga mudah untuk dipahami oleh para pelaut. Hasil dari penelitian ini berupa hasil Analisa blok MPA dan MIO dalam format data vector, point, line dan area dengan struktur data, kodefikasi dan simbol tertentu wilayah Pulau Sangiang dan sekitarnya, sehingga dapat dipergunakan sebagai panduan bagi para pelaut untuk membantu dalam bernavigasi agar meminimalisir kesalahpahaman yang berdampak terhadap terjadinya hal-hal yang tidak diharapkan
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Velez, Gisela, Alexa R. Weingarden, Budd A. Tucker, Hetian Lei, Andrius Kazlauskas, and Michael J. Young. "Retinal Pigment Epithelium and Müller Progenitor Cell Interaction Increase Müller Progenitor Cell Expression of PDGFR and Ability to Induce Proliferative Vitreoretinopathy in a Rabbit Model." Stem Cells International 2012 (2012): 1–6. http://dx.doi.org/10.1155/2012/106486.
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Purpose. Proliferative vitreoretinopathy (PVR) is a complication of retinal detachment characterized by redetachment of the retina as a result of membrane formation and contraction. A variety of retinal cells, including retinal pigment epithelial (RPE) and Müller glia, and growth factors may be responsible. Platelet-derived growth factor receptor alpha (PDGFRα) is found in large quantities in PVR membranes, and is intrinsic to the development of PVR in rabbit models. This study explores the expression of PDGFR in cocultures of RPE and Müller cells over time to examine how these two cell types may collaborate in the development of PVR. We also examine how changes in PDGFRαexpression alter Müller cell pathogenicity.Methods. Human MIO-M1 Müller progenitor (MPC) and ARPE19 cells were studied in a transmembrane coculture system. Immunocytochemistry and Western blot were used to look at PDGFRα, PDGFRβ, and GFAP expression. A transfected MPC line cell line expressing the PDGFRα(MIO-M1α) was generated, and tested in a rabbit model for its ability to induce PVR.Results. The expression of PDGFRαand PDGFRβwas upregulated in MIO-M1 MPCs cocultured with ARPE19 cells; GFAP was slightly decreased. Increased expression of PDGFRαin the MIO-M1 cell line resulted in increased pathogenicity and enhanced ability to induce PVR in a rabbit model.Conclusions. Müller and RPE cell interaction can lead to upregulation of PDGFRαand increased Müller cell pathogenicity. Müller cells may play a more active role than previously thought in the development of PVR membranes, particularly when stimulated by an RPE-cell-rich environment. Additional studies of human samples and in animal models are warranted.
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Azotla-Vilchis, Cuauhtli N., Daniel Sanchez-Celis, Luis E. Agonizantes-Juárez, Rocío Suárez-Sánchez, J. Manuel Hernández-Hernández, Jorge Peña, Karla Vázquez-Santillán, et al. "Transcriptome Analysis Reveals Altered Inflammatory Pathway in an Inducible Glial Cell Model of Myotonic Dystrophy Type 1." Biomolecules 11, no. 2 (January 26, 2021): 159. http://dx.doi.org/10.3390/biom11020159.
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Myotonic dystrophy type 1 (DM1), the most frequent inherited muscular dystrophy in adults, is caused by the CTG repeat expansion in the 3′UTR of the DMPK gene. Mutant DMPK RNA accumulates in nuclear foci altering diverse cellular functions including alternative splicing regulation. DM1 is a multisystemic condition, with debilitating central nervous system alterations. Although a defective neuroglia communication has been described as a contributor of the brain pathology in DM1, the specific cellular and molecular events potentially affected in glia cells have not been totally recognized. Thus, to study the effects of DM1 mutation on glial physiology, in this work, we have established an inducible DM1 model derived from the MIO-M1 cell line expressing 648 CUG repeats. This new model recreated the molecular hallmarks of DM1 elicited by a toxic RNA gain-of-function mechanism: accumulation of RNA foci colocalized with MBNL proteins and dysregulation of alternative splicing. By applying a microarray whole-transcriptome approach, we identified several gene changes associated with DM1 mutation in MIO-M1 cells, including the immune mediators CXCL10, CCL5, CXCL8, TNFAIP3, and TNFRSF9, as well as the microRNAs miR-222, miR-448, among others, as potential regulators. A gene ontology enrichment analyses revealed that inflammation and immune response emerged as major cellular deregulated processes in the MIO-M1 DM1 cells. Our findings indicate the involvement of an altered immune response in glia cells, opening new windows for the study of glia as potential contributor of the CNS symptoms in DM1.
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Bandi, Hari, Dimitris Bertsimas, and Rahul Mazumder. "Learning a Mixture of Gaussians via Mixed-Integer Optimization." INFORMS Journal on Optimization 1, no. 3 (July 2019): 221–40. http://dx.doi.org/10.1287/ijoo.2018.0009.
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We consider the problem of estimating the parameters of a multivariate Gaussian mixture model (GMM) given access to n samples that are believed to have come from a mixture of multiple subpopulations. State-of-the-art algorithms used to recover these parameters use heuristics to either maximize the log-likelihood of the sample or try to fit first few moments of the GMM to the sample moments. In contrast, we present here a novel mixed-integer optimization (MIO) formulation that optimally recovers the parameters of the GMM by minimizing a discrepancy measure (either the Kolmogorov–Smirnov or the total variation distance) between the empirical distribution function and the distribution function of the GMM whenever the mixture component weights are known. We also present an algorithm for multidimensional data that optimally recovers corresponding means and covariance matrices. We show that the MIO approaches are practically solvable for data sets with n in the tens of thousands in minutes and achieve an average improvement of 60%–70% and 50%–60% on mean absolute percentage error in estimating the means and the covariance matrices, respectively, over the expectation–maximization (EM) algorithm independent of the sample size n. As the separation of the Gaussians decreases and, correspondingly, the problem becomes more difficult, the edge in performance in favor of the MIO methods widens. Finally, we also show that the MIO methods outperform the EM algorithm with an average improvement of 4%–5% on the out-of-sample accuracy for real-world data sets.
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Sukumar, Madhusudhanan, Andrea Wilke, Josef Mautner, Hans-Jochem Kolb, Georg Bornkamm, and Armin Gerbitz. "Allogeneic Rejection of High Grade Lymphoma: Evidence for Immune Escape in a Haploidentical Murine Model." Blood 108, no. 11 (November 16, 2006): 3171. http://dx.doi.org/10.1182/blood.v108.11.3171.3171.
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Abstract Allogeneic stem cell transplantation for high grade lymphoma typically suffers from high transplant related mortality and minimal success in achieving long term complete remission. The immunological aspects behind rejection of high grade lymphoma are poorly understood, partly due to the lack of animal models. Using a transgenic mouse lymphoma model, where the proto-oncogene c-myc is driven by parts of the immunoglobulin lambda locus representing a t(8;22) translocation as found in Burkitt’s lymphoma, we developed a haploidentical transplantation model. c-myc-lambda transgenic C57/BL6 mice were crossbred with DBA mice, giving rise to a B6D2F1 generation which develops high grade lymphoma spontaneously within the first 6 months post birth. Primary F1-lymphoma cell lines displayed low MHC class I and class II expression compared to wild type B-cells. When transferred into immune-competent, healthy C57/BL6 parental mice, F1-lymphoma cells were rejected even at high doses of 50 Mio. cells, whereas the syngeneic transfer of 10,000 cells into B6D2F1 mice resulted in 100% mortality due to lymphoma growth. Immunosuppression of C57/BL6 mice by lethal total body irradiation and transplantation of T-cell depleted bone marrow allowed F1-lymphoma to grow when animals were challenged at day +1 after bone marrow transplantation with 1 Mio. cells. Addback of 2.5 or 10 Mio. parental T-cells together with F1-lymphoma on day +1 completely prevented lymphoma growth, and resulted in long term survival for more than 60 days. When T-cell addback was delayed until day +3 or +6 after lymphoma challenge, animals died due to lymphoma progression 7–8 days later. By using “green” T-cells from GFP transgenic C57/BL6 mice we could show that spleens 7 days after T-cell addback contained only 0.5% (15% of total CD3+ cells) GFP positive T-cells, whereas up to 15% (55%–75% of total CD3+ cells) of total splenocytes were GFP positive in long term survivors that rejected lymphoma. Similar results were obtained when T-cells were labelled with CFDA. This indicates that T-cell expansion is associated with lymphoma rejection; animals that receive T-cells after lymphoma has been established do not show any T-cell expansion, even when lymphoma cells display a haplo-mismatch and mature T-cells are co-localized within the spleen. T-Cell expansion is suppressed when lymphoma cells are present in splenic tissue, indicating efficient immune escape. Similar results were observed when bone marrow and T-cells from C57BL/6 donors were transplanted into irradiated B6D2F1 mice and 1 Mio. F1-lymphoma cells were injected on day +1 post transplantation. Despite the presence of GvHD when low number of T-cells (0.5–2.0 Mio.) were used lymphoma growth was measurable and animals eventually died due to disease progression. These results point to the crucial role of pretransplant lymphoma burden for the success of allogeneic stem cell transplantation in high grade lymphoma.
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Meloni, Antonella, Cristina Tassi, Maria Grazia Batzella, Francesca Valeria Commendatore, Giorgio Giannotti, Giuseppe Serra, Petra Keilberg, et al. "Prognostic CMR Parameters For Cardiac Complications In Large Cohort Of Well Treated Thalssemia Major Patients." Blood 122, no. 21 (November 15, 2013): 562. http://dx.doi.org/10.1182/blood.v122.21.562.562.
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Abstract Introduction Cardiac complications are the main cause of death in thalassemia major (TM) patients. Cardiovascular Magnetic Resonance (CMR) plays a key role in their management, assessing myocardial iron overload (MIO), biventricular function, atrial dimensions, and myocardial fibrosis. We evaluated the predictive value of CMR parameters for cardiac complications, including heart failure (HF), arrhythmias and pulmonary hypertension (PH). Methods We followed prospectively 537 white TM patients enrolled in the MIOT network. Fifty patients were excluded from the analysis because a cardiac complication was present at the time of the first CMR. All prognostic variables associated with the outcome at the univariate Cox model were placed in the multivariate model and were ruled out if they did not significantly improve the adjustment. Results At baseline the mean age was 29.5±9.0 years and 222 patients were males. The mean follow-up time was 58±18 months. After the first CMR only the 37.8% of the patients did not change the chelation regimen or the frequency/dosage. Conclusions We detected few cardiac events thanks to a MR-guided, patient-specific adjustment of the chelation therapy. Severe and homogeneous MIO, myocardial fibrosis and ventricular dysfunction identify patients at high risk of heart failure. Heart T2* doesn’t have any power in predicting arrhythmias while male sex and atrial dilation are independent prognosticators. Male sex, severe and homogeneous MIO, myocardial fibrosis and ventricular dysfunction identify patients at high risk of cardiac complications globally considered. Disclosures: No relevant conflicts of interest to declare.
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Pahor, A. L., and J. M. Stansbie. "The Midland Institute of Otology and its Founder: William Stirk Adams (1896–1978)." Journal of Laryngology & Otology 111, no. 12 (December 1997): 1122–25. http://dx.doi.org/10.1017/s0022215100139519.
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AbstractTo celebrate the 50th Anniversary of the establishment of the Midland Institute of Otology (MIO) a. meeting was held in the Belfry Hotel, West Midlands, 19–21 September 1997. The meeting comprised an excellent academic conference, social events and a golf tournament. A report on the academic conference has been published (Stansbie and Pahor, 1997).The MIO has been established to further the cause of ENT in the Midlands and it has succeeded in its aim to a great extent. An historical overview of the Institute is of interest and would serve perhaps as a model for similar organizations, especially in the provinces.The Institute was the brainchild of William Stirk Adams. He remained the President from the conception of the Institute till his death.It is befitting to present a biography of such a dedicated personality.
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Prado Saldanha, Fabio, Patrick Cohendet, and Marlei Pozzebon. "Challenging the Stage-Gate Model in Crowdsourcing: The Case of Fiat Mio in Brazil." Technology Innovation Management Review 4, no. 9 (September 23, 2014): 28–35. http://dx.doi.org/10.22215/timreview829.
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Prado Saldanha, Fabio, Patrick Cohendet, and Marlei Pozzebon. "Challenging the Stage-Gate Model in Crowdsourcing: The Case of Fiat Mio in Brazil." Technology Innovation Management Review 4, no. 9 (September 23, 2014): 28–35. http://dx.doi.org/10.22215/timreview/829.
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Zheng, Bang Gui, Yi Bin Huang, and Cong Ying Qiu. "LQR+PID Control and Implementation of Two-Wheeled Self-Balancing Robot." Applied Mechanics and Materials 590 (June 2014): 399–406. http://dx.doi.org/10.4028/www.scientific.net/amm.590.399.
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A two-wheeled self-balancing robot system is designed, which uses TMS320LF2407DSP as the controller and Mio-x AHRS module as the main sensor. The dynamic model of robot is analyzed by state space model and transfer function. Robot’s physical system control is guided by the result from simulation experiments. A LQR+PID control method is put forward by comparing advantages and disadvantages of LQR control and PID control. The experiments result shows that this control method cuts down the design cycle, and also has a strong robustness. It is suitable for the multi-variable, high-rank, strongly coupling, non-linear two-wheeled self-balancing robot control.
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Bull, Natalie D., G. Astrid Limb, and Keith R. Martin. "Human Müller Stem Cell (MIO-M1) Transplantation in a Rat Model of Glaucoma: Survival, Differentiation, and Integration." Investigative Opthalmology & Visual Science 49, no. 8 (August 1, 2008): 3449. http://dx.doi.org/10.1167/iovs.08-1770.
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Meloni, Antonella, Lucia De Franceschi, Domenico Maddaloni, Sabrina Carollo, Roberto Sarli, Carlo Cosmi, Giovan Battista Ruffo, et al. "Left Ventricular Global Function Index and Left Ventricular Mass Volume Ratio By CMR: Relation with Heart Failure in Thalassemia Major Patients." Blood 124, no. 21 (December 6, 2014): 2688. http://dx.doi.org/10.1182/blood.v124.21.2688.2688.
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Abstract Introduction: Recently two novels indicators of left ventricular (LV) performance assessed by Cardiovascular Magnetic Resonance (CMR) have been introduced: the LV global function index (LVGFI) and the LV mass/volume ratio (LVMVR). The LVGFI combines LV stroke volume, end-systolic and end diastolic volumes, as well as LV mass, integrating structural as well as mechanical behaviour. Elevated LVMVR is indicative of concentric remodelling. A LVGFI <37% and a LVMVR>1 were shown to be associated with the occurrence of cardiovascular events in no-thalassemic populations. This retrospective cohort study aimed to systematically evaluate in a large historical cohort of thalassemia major (TM) in the CMR era whether the LVGFI and the LVMVR were associated with a higher risk of heart failure. Methods: We considered 812 TM patients (391 M, 30.4±8.6 years), consecutively enrolled in the Myocardial Iron Overload in Thalassemia (MIOT) network. LVGFI and LVMRI were quantitatively evaluated by SSFP cine images. The T2* value in all the 16 cardiac segments was evaluated and a global heart T2* value <20 ms was considered indicative of myocardial iron overload (MIO). Results: Eighty (9.9%) patients had a LVGFI<37% and, compared to the patients with a normal LVGFI, they showed a significant higher frequency of heart failure (43.8% vs 4.2%; P<0.0001). Patients with a LVGFI<37% had a significant higher risk of heart failure (odds-ratio-OR=17.59, 95%CI=9.95-21.09; P=<0.001). The risk remained significant also adjusting for the presence of MIO (OR=15.54, 95%CI=8.05-26.27; P=<0.001). Thirty (3.7%) patients had a LVMVR≥1% and, compared to the patients with a normal LVMRI, they showed a significant higher frequency of heart failure (20.0% vs 7.7%; P=0.015). Patients with a LVMVR≥1% had a significant higher risk of heart failure (OR=3.01, 95%CI=1.18-7.64; P=0.021). The risk remained significant also adjusting for the presence of MIO (OR=3.44, 95%CI=1.31-9.01; P=0.012). In a multivariate model including LVGFI, LVMVR and heart iron, the significant predictors of heart failure were a LVGFI<37% (OR=14.05, 95%CI=7.66-25.77; P=<0.001) and a global heart T2*<20 ms (OR=1.94, 95%CI=1.08-3.47; P=0.026). Conclusions: In TM patients a LVGFI<37% was associated with an higher risk of heart failure, independent by the presence of MIO. A widespread program using CMR exploiting its multi-parametric potential can have considerable power for the early identification and treatment of patients at risk for heart failure. Disclosures No relevant conflicts of interest to declare.
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Meloni, Antonella, Gaetano Giuffrida, Cristina Paci, Leonardo Sardella, Alessandra Quota, Pier Paolo Bitti, Lucia De Franceschi, et al. "Left and Right Ventricular Wall Motion Abnormalities In Thalassemia Major Patients." Blood 122, no. 21 (November 15, 2013): 2255. http://dx.doi.org/10.1182/blood.v122.21.2255.2255.
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Abstract Introduction Left ventricular (LV) and right ventricular (RV) wall motion abnormalities can be detected through a qualitative analysis of cine magnetic resonance (MR) images. Moreover, MR is the gold standard technique for the evaluation of myocardial iron overload (MIO), biventricular global systolic function and myocardial fibrosis. We investigated the relationships between LV movement abnormalities and MIO, LV function and myocardial fibrosis as well as between RV motion and function in thalassemia major (TM) patients. Methods CMR was performed in 1092 TM patients (537 male; 30.6±8.5 years) enrolled in the Myocardial Iron Overload in Thalassemia Network. Cine images were acquired to evaluate wall motion and to quantify biventricular volumes and ejection fraction (EF). For MIO assessment, a T2* multislice approach was used. To detect myocardial fibrosis, late gadolinium enhanced (LGE) images were acquired. For the LV the 16-segment model of the AHA/ACC was taken into account during image analysis: wall motion, T2* value and presence/absence of enhancing area were evaluated for each segment. Results Abnormal motion of LV was found in 66 (6%) patients (60 hypokinetic and 6 dyskinetic). Table 1 shows the comparison between TM patients with normal and abnormal LV motion. Patients with abnormal LV motion were older and had significantly lower global T2* value and significantly higher number of segments with T2*<20 ms. Left volumes and mass indexed by body surface area were significantly higher in patients with abnormal LV motion while the EF was significantly lower. LGE areas were detected in 196 patients (18%) and were predominantly located in the mid-ventricular septum. There was a significant correlation between LGE and abnormal LV motion. Abnormal motion of the RV was found in 35 (3.2%) patients (29 hypokinetic, 5 dyskinetic and 1 akynetic). Table 2 shows the comparison between TM patients with normal and abnormal RV motion. Patients with abnormal RV motion were older and they were more frequently males. Right volumes were significantly higher in patients with abnormal RV motion while the EF was significantly lower. Abnormal LV motion was not correlated with abnormal RV motion. Seventeen patients showed movement abnormalities in both ventricles. Conclusions Movement abnormalities in the left ventricle were not really frequent in TM patients but were associated with age, MIO, LV dilation and dysfunction, and myocardial fibrosis. Movement abnormalities in the right ventricle were less frequent compared to the left ventricle, but were associated with age, sex , RV dilation and dysfunction. Disclosures: No relevant conflicts of interest to declare.
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Kuhlmann, Alexander, Henning Krüger, Susanne Seidinger, and Andreas Hahn. "Cost-effectiveness and budget impact of the microprocessor-controlled knee C-Leg in transfemoral amputees with and without diabetes mellitus." European Journal of Health Economics 21, no. 3 (January 2, 2020): 437–49. http://dx.doi.org/10.1007/s10198-019-01138-y.
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Abstract Background The safe use of a prosthesis in activities of daily living is key for transfemoral amputees. However, the number of falls varies significantly between different prosthetic device types. This study aims to compare medical and economic consequences of falls in transfemoral amputees who use the microprocessor-controlled knee joint C-Leg with patients who use non-microprocessor-controlled (mechanical) knee joints (NMPK). The main objectives of the analysis are to investigate the cost-effectiveness and budget impact of C-Legs in transfemoral amputees with diabetes mellitus (DM) and without DM in Germany. Methods A decision-analytic model was developed that took into account the effects of prosthesis type on the risk of falling and fall-related medical events. Cost-effectiveness and budget impact analyses were performed separately for transfemoral amputees with and without DM. The study took the perspective of the statutory health insurance (SHI). Input parameters were derived from the published literature. Univariate and probabilistic sensitivity analyses (PSA) were performed to investigate the impact of changes in individual input parameter values on model outcomes and to explore parameter uncertainty. Results C-Legs reduced the rate of fall-related hospitalizations from 134 to 20 per 1000 person years (PY) in amputees without DM and from 146 to 23 per 1000 PY in amputees with DM. In addition, the C-Leg prevented 15 or 14 fall-related death per 1000 PY. Over a time horizon of 25 years, the incremental cost-effectiveness ratio (ICER) was 16,123 Euro per quality-adjusted life years gained (QALY) for amputees without DM and 20,332 Euro per QALY gained for amputees with DM. For the period of 2020–2024, the model predicted an increase in SHI expenditures of 98 Mio Euro (53 Mio Euro in prosthesis users without DM and 45 Mio Euro in prosthesis users with DM) when all new prosthesis users received C-Legs instead of NMPKs and 50% of NMPK user whose prosthesis wore out switched to C-Legs. Results of the PSA showed moderate uncertainty and a probability of 97–99% that C-Legs are cost-effective at an ICER threshold of 40,000 Euro (≈ German GDP per capita in 2018) per QALY gained. Conclusion Results of the study suggest that the C-Leg provides substantial additional health benefits compared with NMPKs and is likely to be cost-effective in transfemoral amputees with DM as well as in amputees without DM at an ICER threshold of 40,000 Euro per QALY gained.
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Kurtz, W., G. He, S. Kollet, R. Maxwell, H. Vereecken, and H. J. Hendricks Franssen. "TerrSysMP-PDAF (version 1.0): a modular high-performance data assimilation framework for an integrated land surface–subsurface model." Geoscientific Model Development Discussions 8, no. 11 (November 3, 2015): 9617–68. http://dx.doi.org/10.5194/gmdd-8-9617-2015.
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Abstract. Modelling of terrestrial systems is continuously moving towards more integrated modelling approaches where different terrestrial compartment models are combined in order to realise a more sophisticated physical description of water, energy and carbon fluxes across compartment boundaries and to provide a more integrated view on terrestrial processes. While such models can effectively reduce certain parameterization errors of single compartment models, model predictions are still prone to uncertainties regarding model input variables. The resulting uncertainties of model predictions can be effectively tackled by data assimilation techniques which allow to correct model predictions with observations taking into account both the model and measurement uncertainties. The steadily increasing availability of computational resources makes it now increasingly possible to perform data assimilation also for computationally highly demanding integrated terrestrial system models. However, as the computational burden for integrated models as well as data assimilation techniques is quite large, there is an increasing need to provide computationally efficient data assimilation frameworks for integrated models that allow to run on and to make efficient use of massively parallel computational resources. In this paper we present a data assimilation framework for the land surface–subsurface part of the Terrestrial System Modelling Platform TerrSysMP. TerrSysMP is connected via a memory based coupling approach with the pre-existing parallel data assimilation library PDAF (Parallel Data Assimilation Framework). This framework provides a fully parallel modular environment for performing data assimilation for the land surface and the subsurface compartment. A simple synthetic case study for a land surface–subsurface system (0.8 Mio. unknowns) is used to demonstrate the effects of data assimilation in the integrated model TerrSysMP and to access the scaling behaviour of the data assimilation system. Results show that data assimilation effectively corrects model states and parameters of the integrated model towards the reference values. Scaling tests provide evidence that the data assimilation system for TerrSysMP can make efficient use of parallel computational resources for > 30 k processors. Simulations with a large problem size (20 Mio. unknows) for the forward model were also efficiently handled by the data assimilation system. The proposed data assimilation framework is useful in simulating and estimating uncertainties in predicted states and fluxes of the terrestrial system over large spatial scales at high resolution utilizing integrated models.
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Rebholz, Sandra L., Thomas Jones, Katie T. Burke, Anja Jaeschke, Patrick Tso, David A. D'Alessio, and Laura A. Woollett. "Multiparity leads to obesity and inflammation in mothers and obesity in male offspring." American Journal of Physiology-Endocrinology and Metabolism 302, no. 4 (February 15, 2012): E449—E457. http://dx.doi.org/10.1152/ajpendo.00487.2011.
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Multiparity is an independent risk factor for obesity in parous females. In addition to being a health issue for the mother, offspring of multiparous females may also be at risk for obesity later in life. The aim of the current study was to establish a mouse model that mimics the human pathology of multiparity and determine the effects of multiparity-induced obesity (MIO) on offspring in adulthood. C57BL/6 mice were mated and studied when primiparous (1st pregnancy) or multiparous (4th pregnancy). Dams became obese with multiparity, an effect that was independent of the age of the dam. Multiparous dams also had increased markers of inflammation (JNK activation, cytokine expression) in adipose tissue and liver that was greater than inflammation in nulliparous females made obese with a high-fat diet. Placental inflammation was prevalent in multiparous vs. primiparous dams as well. Male offspring of the multiparous dams developed increased adiposity by 24 wk of age relative to the progeny of primiparous dams, although food consumption was similar in both groups. Lipid metabolism was altered in liver and fat in that mRNA levels of regulatory genes (PGC-1α) as well as metabolic genes (CPT I) and Akt phosphorylation were decreased in offspring of multiparous dams. Thus, in mice, as in humans, multiparity increases adiposity and is associated with hepatic and placental inflammation and abnormal glucose tolerance. Importantly, MIO leads to increased body fat and metabolic dysfunction in the offspring, suggesting a role in the propagation of obesity.
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Jarray, Hanen, Mounira Zammouri, Mohamed Ouessar, Ammar Zerrim, and Houcine Yahyaoui. "GIS based DRASTIC model for groundwater vulnerability assessment: Case study of the shallow mio-plio-quaternary aquifer (Southeastern Tunisia)." Water Resources 44, no. 4 (July 2017): 595–603. http://dx.doi.org/10.1134/s0097807817040066.
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Sartori, M., F. Baillifard, M. Jaboyedoff, and J. D. Rouiller. "Kinematics of the 1991 Randa rockslides (Valais, Switzerland)." Natural Hazards and Earth System Sciences 3, no. 5 (October 31, 2003): 423–33. http://dx.doi.org/10.5194/nhess-3-423-2003.
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Abstract. About 22 mio m3 of rock fell from a cliff near the village of Randa (10 km north of Zermatt, Switzerland) on 18 April 1991. A second retrogressive rockslide of about 7 mio m3 followed on 9 May 1991. At present, a rock mass situated above the scarp is still slowly moving toward the valley, involving several mio m 3 of rock. A kinematic approach to study of this well-documented rockslide was made "a posteriori" in order to identify the parameters relevant to the detection of such failures involving large volumes of rock. A 3-D model of the pre-rockslide geometry is presented, and is used to interpret the geostructural, hydrogeological, and chronological data. The steepness of the cliff, the massive lithology (mainly orthogneiss), the location on a topographic ridge outcropping at the confluence between a glacial cirque and the main valley, and the existence of previous events of instability were the preexisting field conditions that affected the stability of the area. The structural cause of instability was a 30 dipping, more than 500-m-long, persistent fault, which cut the base of the rock face. Together with a steeply dipping set of persistent joints, this basal discontinuity delimited a 20- mio-m 3 rock block, with a potential sliding direction approximately parallel to the axis of the valley. To the North, the fractures delimiting the unstable mass were less persistent and separated by rock bridges; this rock volume acted as key block. This topographic and structural configuration was freed from glacier support about 15 000 years BP. The various mechanisms of degradation that led to the final loss of equilibrium required various amounts of time. During the late-and post-glacial periods, seismic activity and weathering of the orthogneiss along the fissure network due to infiltration of meteoric water, joined to reduce the mechanical resistance of the sliding surfaces and the rocks bridges. In addition, crystallisation of clay minerals due to mineralogical alteration of the fault gouge accumulated along the sliding surface, reducing its angle of internal friction, and sealing the surface against water circulation. Once this basal fracture began to act as an aquiclude, the seasonal increase of the hydraulic head in the fissures promoted hydraulic fracturing on the highly stressed edges of the key block. Acceleration of this mechanical degradation occurred during the 20-year period before the 1991 rockslides, giving rise to an increasing rockfall activity, that constituted a forewarning sign. The final triggering event corresponded to a snow-melt period with high water table, leading to fracturation around the key block. On 18 April 1991, the key block finally failed, allowing subsidiary orthogneiss blocks to slide. They fell in turn over a period of several hours. The 9 May 1991, rockslide was the first of a series of expected future retrogressive reequilibrium stages of the very fractured and decompressed paragneisses, which lie on the orthogneiss base cut by the 18 April event.
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Rahman, Maulana, and Nawa Suhayani. "Analisis Differensiasi Produk dan Citra Merek terhadap Keputusan Pembelian Konsumen pada Sepeda Motor Merek Yamaha Mio di Kota Langsa." Jurnal Samudra Ekonomi dan Bisnis 11, no. 2 (June 21, 2020): 227–36. http://dx.doi.org/10.33059/jseb.v11i2.2195.
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This study aims to analyze product differentiation and brand image on the customer purchase decision, with a case study of the Yamaha Mio brand of matic-bike in Langsa City. Multiple regression method was used to analyze data.. The results showed that partially, product differentiation and brand image had a positive and significant influence on consumer purchasing decisions. Simultaneously, the two independent variables were also obtained to have a significant influence on dependent variable. Thus, if the company implements strategies related to product differentiation and brand image, partially or simultaneously, it will strengthen the purchasing decisions made by consumers for products offered. However, the determination analysis identifies that there are several main factors that are considered to influence consumer purchasing decisions but are not included in this research model.
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Meloni, Antonella, Patrizia Toia, Leonardo Sardella, Giuseppe Serra, Roberta Chiari, Alfonso D'Ambrosio, Lucia De Franceschi, et al. "Pericardial Effusion Is a Marker of Increased Mortality in Thalassemia Major Patients." Blood 124, no. 21 (December 6, 2014): 2689. http://dx.doi.org/10.1182/blood.v124.21.2689.2689.
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Abstract Introduction. In different types of not-hematological diseases the presence of a small pericardial effusion (PE) was associated with worse survival even after adjustment for patient characteristics, suggesting that it is a marker of underlying disease.In thalassemia major (TM) pericardial effusion was shown to be one of the manifestations of heart disease but its potential prognostic importance has never been investigated in the modern era. Cardiovascular Magnetic Resonance (CMR) by cine SSFP sequences was demonstrated to be extremely sensitive to even a small amount of PE. This is the first prospective study evaluating if the presence of pericardial effusion is associated with increased mortality in TM. Methods. 1259 patients (648 females, mean age 31.02 ± 8.64 years) enrolled in the Myocardial Iron Overload in Thalassemia (MIOT) were prospectively followed from their first Magnetic Resonance Imaging (MRI) scan. CMR was used to quantify myocardial iron (MIO) overload by a multislice multiecho T2* approach and to assess biventricular function parameters and to detect PE by cine SSFP sequences. Results. PE was present in 25 (2.0%) patients.Patients with and without PE were comparable for age and ratio of men/women. At the baseline, the percentage of patients with MIO (global heart T2* value < 20 ms) was comparable between patients with and without PE (12.0 % vs 28.7%; P=0.074) and left ventricular and right ventricular ejection fractions were not significantly different between the two groups. Mean follow-up (FU) time was 44.55 ± 20.35 months and there were 15 deaths. Mortality was greater for patients with PE compared to those without an effusion (8.0% vs 1.1%, P=0.034). PE was a significant predictive factor for death (hazard ratio-HR=12.64, 95%CI=2.78-57.42, P=0.001). PE remained a significant prognosticator for death also in a multivariate model including MIO ms (PE: HR=17.36, 95%CI=3.65-82.62, P<0.0001and global heart T2* < 20 ms: HR=3.07, 95%CI=1.07-8.75, P=0.036). Conclusions. PE is quite rare in TM patients and it is not related to myocardial iron overload. An important role in the development of PE could be played by the 'iron-induced' pericardial siderosis but, due to the limitations of the current non-invasive CMR techniques, we were not able to address this issue. PE was found to be a strong predictor for death, independently by the presence of myocardial iron overload. The non-invasive diagnosis of pericardial effusion is important for a more complete definition of the cardiac involvement of TM patients. The increased risk of death associated with PE may be used along with other clinical characteristics when estimating a patient's prognosis and monitoring. Disclosures Pepe: Chiesi: Speakers Bureau; ApoPharma Inc.: Speakers Bureau; Novartis: Speakers Bureau.
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Nehm, Ross H., and Dana H. Geary. "A gradual morphologic transition during a rapid speciation event in marginellid gastropods (Neogene: Dominican Republic)." Journal of Paleontology 68, no. 4 (July 1994): 787–95. http://dx.doi.org/10.1017/s0022336000026226.
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We document a speciation event between two species of Prunum (Marginellidae: Gastropoda) in Pliocene strata of the northern Dominican Republic. The ancestral species, P. coniforme, is widely distributed in the Mio-Pliocene of the Dominican Republic and Jamaica, and has a range of at least 11 m.y. The descendant species, P. christineladdae, is endemic to the northern Dominican Republic. The ancestral species persists after its descendant arises. The transition between species is marked by stratigraphic and morphologic intermediates, and occurs during an interval estimated to be between 73,000 and 275,000 years (representing 0.6-2.5 percent of the duration of the ancestral species). Although the transition takes more than a geologic instant, the overall pattern of morphologic change is best described by the model of punctuated equilibrium. The change between species apparently involved a habitat shift into deeper water, and occurred during accelerated deepening. All of the Neogene Dominican species of Prunum appear to have had depth-defined ranges.
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Sedrati, N., and L. Djabri. "Contribution of hydrochemistry to the characterization and assessment of groundwater resources: the case of Tebessa alluvial aquifer (Algeria)." Proceedings of the International Association of Hydrological Sciences 364 (September 16, 2014): 458–63. http://dx.doi.org/10.5194/piahs-364-458-2014.
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Abstract. Assessment of groundwater resources requires the knowledge of geometric and hydrodynamic features. In the Mio-Plio-Quaternary aquifer of the plain of Tebessa (Algeria), the groundwater quality is deteriorating. Different methods using geochemistry (ions Na+, Cl−, SO42−, NO3−) and conductivity are compared with the hydrogeological information to identify the main processes involved in the increase in pollution. The evaluation for water contamination is based on the method proposed by Tolga et al. (2009) for irrigation waters, and on that proposed by Neubert et al. (2008), for those intended for drinking water supply. This method is a new technique of indexation of water sensitivity to pollution. It combines data from water chemistry and the results obtained by applying the DRASTIC model to the area of study. The obtained maps of sensitivity reveal zones that coincide almost perfectly with those of strong anthropogenic activities. Suitable water management policies are needed to save this unconfined aquifer and provide the data necessary to define the area at increased risk from these phenomena.
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Roopnarine, Peter D. "The description and classification of evolutionary mode: a computational approach." Paleobiology 27, no. 3 (2001): 446–65. http://dx.doi.org/10.1666/0094-8373(2001)027<0446:tdacoe>2.0.co;2.
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The incorporation of the random walk model into stratophenetic analysis marked a turning point by presenting a potential null model for microevolutionary patterns. Random walks are derived from a family of statistical fractals, and their statistics can be reconstructed using appropriate techniques. This paper lays the foundation for the explicit and uniform description of evolutionary mode in stratophenetic series using random walk null models and the information contained within incompletely preserved time series.The method relies upon the iterative analysis of subseries of an original stratophenetic series by measuring the presence of deviations from statistical randomness as the lineage evolves. This measure, and its probability of significance (evaluated using a randomization test), forms the dimensions of a descriptive space for microevolutionary modes. Each stratophenetic series can then be viewed as a journey through this space. Computer simulation of various evolutionary modes demonstrates that different modes, for example stasis and gradualism, have differing trajectories and occupy different regions of the microevolutionary space. The method is applied to two published foraminiferal stratophenetic series, the Mio-Pliocene Globorotalia plesiotumida-tumida punctuated transition and an anagenetic trend in the Late Cretaceous Contusotruncana fornicata-contusa lineage. An anagenetic trend is strongly supported in the latter example, whereas transformation of the Globorotalia species seems to result from the fluctuating effectiveness of constraining processes.
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Staudt, Yves, and Joël Wagner. "Assessing the Performance of Random Forests for Modeling Claim Severity in Collision Car Insurance." Risks 9, no. 3 (March 16, 2021): 53. http://dx.doi.org/10.3390/risks9030053.
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For calculating non-life insurance premiums, actuaries traditionally rely on separate severity and frequency models using covariates to explain the claims loss exposure. In this paper, we focus on the claim severity. First, we build two reference models, a generalized linear model and a generalized additive model, relying on a log-normal distribution of the severity and including the most significant factors. Thereby, we relate the continuous variables to the response in a nonlinear way. In the second step, we tune two random forest models, one for the claim severity and one for the log-transformed claim severity, where the latter requires a transformation of the predicted results. We compare the prediction performance of the different models using the relative error, the root mean squared error and the goodness-of-lift statistics in combination with goodness-of-fit statistics. In our application, we rely on a dataset of a Swiss collision insurance portfolio covering the loss exposure of the period from 2011 to 2015, and including observations from 81 309 settled claims with a total amount of CHF 184 mio. In the analysis, we use the data from 2011 to 2014 for training and from 2015 for testing. Our results indicate that the use of a log-normal transformation of the severity is not leading to performance gains with random forests. However, random forests with a log-normal transformation are the favorite choice for explaining right-skewed claims. Finally, when considering all indicators, we conclude that the generalized additive model has the best overall performance.
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Москаленко, В’ячеслав Васильович, Микола Олександрович Зарецький, and Альона Сергіївна Москаленко. "МОДЕЛЬ ТА МЕТОД НАВЧАННЯ СИСТЕМИ КЛАСИФІКАЦІЇ РУХОМИХ ОБ’ЄКТІВ ДЛЯ МАЛОГАБАРИТНОГО БЕЗПІЛОТНОГО АПАРАТУ." RADIOELECTRONIC AND COMPUTER SYSTEMS, no. 2 (June 21, 2019): 108–17. http://dx.doi.org/10.32620/reks.2019.2.10.
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The classification model which consists of the motion detector, object tracker, convolutional sparse coded feature extractor and stacked information-extreme classifier is developed. It is proposed to build a motion detector based on the difference of consecutive aligned frames where alignment is performed via keypoints matching, homography estimation, and projective transformations. Motion detector seeks to simplify object classification task through reduction of input data variations and resource savings for motion region search model synthesis without training. The proposed model is characterized by low computational complexity and it can be used as labeling dataset gathering tool for deep moveable object detector. Furthermore, the training method for moving object detector is developed. The method consisting in unsupervised pretraining feature extractor based on sparse coding neural gas, supervised pretraining and following fine-tuning of stacked information-extreme classifier. Using soft-competitive learning scheme in sparse coding neural gas facilitates robust convergence to close to optimal distributions of the neurons over the data. Sparse coding neural gas reduces the requirements for the volume of labeled observations and computational resource. As a criterion for the effectiveness of classifier's machine training, the normalized modification of S. Kullback’s information measure is considered. Labeling new emerging data through self-labeling for high prediction score cases and manual labeling for low prediction score cases, and following labeled object tracking are also offered. In this case, class balancing using undersampling within dichotomous strategy “one-against-all”. The set of classes include bicycle, bus, car, motorcycle, pickup truck, articulated truck, and background. Simulation results on MIO-TCD dataset confirm the suitability of the proposed model and training method for practical usage.
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Pollak, Hans, Michael Fischer, Stephan Fritsch, and Wolfgang Enenkel. "Are Admission Plasma Fibrinogen Levels Useful in the Characterization of Risk Groups after Myocardial Infarction Treated with Fibrinolysis?" Thrombosis and Haemostasis 66, no. 04 (1991): 406–9. http://dx.doi.org/10.1055/s-0038-1646428.
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SummaryThe aim of our study was to prove or disprove the independent prognostic importance of fibrinogen after myocardial infarction. Plasma fibrinogen levels were determined on admission in 135 patients with an acute myocardial infarction and symptoms up to 4 h (mean: 1.8 h) immediately before starting fibrinolytic treatment with 1.5 mio U. streptokinase i.v. All patients were free from other diseases which are known to cause elevated fibrinogen levels. Coronary angiography was carried out in 87%. During a mean follow-up period of 26.2 months 31 coronary events could be observed in 26 patients: 18 reinfarctions, 6 cases of sudden death, and 7 coronary artery bypass graft surgeries because of new symptoms. While plasma fibrinogen levels were higher in smokers than in non-smokers (3.30 vs 2.94 g/l p = 0.011) and correlated with the number of involved coronary arteries (p = 0.08), values were similar in patients with and without coronary events during follow-up (3.07 vs 3.16 g/l, p = 0.70). This applied as well to univariate analysis as to multivariate Cox's regression model. We conclude that plasma fibrinogen levels determined very early in patients with acute myocardial infarction do correlate with other important prognostic variables, but have no independent prognostic importance.
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Contoux, C., A. Jost, G. Ramstein, P. Sepulchre, G. Krinner, and M. Schuster. "Impact of the Megalake Chad on climate and vegetation during the late Pliocene and the mid-Holocene." Climate of the Past Discussions 9, no. 2 (March 11, 2013): 1363–96. http://dx.doi.org/10.5194/cpd-9-1363-2013.
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Abstract. Given the growing evidence for megalakes in the geological record, assessing their impact on climate and vegetation is important for the validation of paleoclimate simulations and therefore the accuracy of model/data comparison in lacustrine environments. Megalake Chad (MLC) occurrences are documented for the mid-Holocene but also for the Mio-Pliocene (Schuster et al., 2009). The surface covered by water would have reached up to ~350 000 km2 (Ghienne et al., 2002; Schuster et al., 2005; Leblanc et al., 2006) making it an important evaporation source, possibly modifying the climate and vegetation in the Chad basin. We investigated the impact of such a giant continental water area in two different climatic backgrounds within the Paleoclimate Model Intercomparison Project phase 3 (PMIP3): the late Pliocene (3.3 to 3 Ma, i.e. the mid-Piacenzian warm period) and the mid-Holocene (6 kyr BP). In all simulations including a MLC, precipitation is drastically reduced above the lake surface because deep convection is inhibited by colder air above the lake surface. Meanwhile, convective activity is enhanced around the MLC, because of the wind increase generated by the flat surface of the megalake, transporting colder and moister air towards the eastern shore of the lake. Effect of the MLC on precipitation and temperature is not sufficient to widely impact vegetation patterns. Nevertheless, tropical savanna is present in the Chad Basin in all climatic configurations, even without the MLC presence, showing that the climate itself is the driver of favourable environments for sustainable hominid habitats.
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Contoux, C., A. Jost, G. Ramstein, P. Sepulchre, G. Krinner, and M. Schuster. "Megalake Chad impact on climate and vegetation during the late Pliocene and the mid-Holocene." Climate of the Past 9, no. 4 (July 5, 2013): 1417–30. http://dx.doi.org/10.5194/cp-9-1417-2013.
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Abstract. Given the growing evidence for megalakes in the geological record, assessing their impact on climate and vegetation is important for the validation of palaeoclimate simulations and therefore the accuracy of model–data comparison in lacustrine environments. Megalake Chad (MLC) occurrences are documented not only for the mid-Holocene but also for the Mio-Pliocene (Schuster et al., 2009). At this time, the surface covered by water would have reached up to ~350 000 km2 (Ghienne et al., 2002; Schuster et al., 2005; Leblanc et al., 2006), making it an important evaporation source, possibly modifying climate and vegetation in the Chad Basin. We investigated the impact of such a giant continental water area in two different climatic backgrounds within the Paleoclimate Model Intercomparison Project phase 3 (PMIP3): the late Pliocene (3.3 to 3 Ma, i.e. the mid-Piacenzian warm period) and the mid-Holocene (6 kyr BP). In all simulations including MLC, precipitation is drastically reduced above the lake surface because deep convection is inhibited by overlying colder air. Meanwhile, convective activity is enhanced around MLC because of the wind increase generated by the flat surface of the megalake, transporting colder and moister air towards the eastern shore of the lake. The effect of MLC on precipitation and temperature is not sufficient to widely impact vegetation patterns. Nevertheless, tropical savanna is present in the Chad Basin in all climatic configurations, even without MLC presence, showing that the climate itself is the driver of favourable environments for sustainable hominid habitats.
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Pepe, Alessia, Laura Pistoia, Nicola Martini, Daniele De Marchi, Andrea Barison, Aurelio Maggio, Piera Giovangrossi, et al. "Detection of Myocardial Iron Overload with Magnetic Resonance By Native T1 and T2* Mapping Using a Segmental Approach." Blood 132, Supplement 1 (November 29, 2018): 2346. http://dx.doi.org/10.1182/blood-2018-99-112559.
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Abstract Introduction. T2* measurement of myocardial iron overload (MIO) is presently the gold standard for monitoring and tailoring the chelation in thalassemia patients. Native T1 mapping has been proposed also for the MIO quantification because it is known that iron can reduce native T1 values. No data are available in literature comparing T1 and T2* mapping using a segmental approach including the whole left ventricle. The goal of our study was to assess the relationship between T1 and T2* values using a segmental approach. Methods. 29 patients with hemoglopinopathies (18 females, 45.39±13.49 years) enrolled in the Extension Myocardial Iron Overload in Thalassemia (eMIOT) Network were considered. Native T1 and T2* images were acquired, respectively, with the Modified Look-Locker Inversion recovery (MOLLI) and with the multi-echo gradient-echo techniques. Three parallel short-axis views (basal, medium and apical) of the left ventricle (LV) were acquired with ECG-gating. The myocardial T1 and T2* distribution was mapped into a 16-segment LV model, according to the AHA/ACC model. The lower limit of normal for each segment was established as mean±2 standard deviations on data acquired on 14 healthy volunteers. In 25 patients also post-contrastografic images were acquired. Results. T1 images showed more pronounced motion artifacts and lower contrast-to-noise-ratio, determining the exclusion of 18/464 segments. No segments were excluded by T2* mapping. So, globally, 446 segmental T1 and T2* values were considered. The mean of all segmental T2* and T1 values were, respectively, 37.83±11.30 ms and 982.72±118.24 ms. Normal T2* and T1 values were found in 374 segments (83.9%) while 29 (6.5%) segments had pathologic T2* and T1 values. For 33 segments (7.4%) (13 patients) a pathologic T1 value was detected in presence of a normal T2* value. For 10 segments (2.2%) a pathologic T2* value was detected in presence of a normal T1 value. Out of the 9 patients with pathologic T2* values in presence of normal T1, in 7 patients post-contrastografic images were acquired; in all segments with pathologic T2* value macroscopic fibrosis by late gadolinium enhancement technique and/or microscopic fibrosis by T1 mapping were found. The relation between segmental T1 and T2* values is shown in the figure. For patients with pathologic segmental T2* values there was a linear relationship between T1 and T2* values (R=0.735, P<0.0001) while the whole data was fitted with a quadratic curve. Conclusion. T2* and T1 mapping showed a good correlation in identifying iron by a segmental approach. However, we found a scatter between results. In 9 patients T1 mapping was not able to detect iron probably due to the presence of macroscopic and/or microscopic fibrosis that it is known to increase the native T1 . Conversely, in 13 patients T1 mapping seems to be more sensitive than T2* (sensitive to different iron chemistry or error measurements?). Further studies on larger population and correlation with clinical outcome are need. Figure. Figure. Disclosures Pepe: Chiesi Farmaceutici S.p.A., ApoPharma Inc., and Bayer: Other: No profit support.
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Whitelaw, J. L., K. Mickus, M. J. Whitelaw, and J. Nave. "High-resolution gravity study of the Gray Fossil Site." GEOPHYSICS 73, no. 2 (March 2008): B25—B32. http://dx.doi.org/10.1190/1.2829987.
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The Gray Fossil Site, Washington County, Tennessee, has produced a remarkable Mio-Pliocene fauna and flora with no known correlative in the Appalachian region. After its discovery in 2000, a series of auger holes were drilled by the Tennessee Department of Transportation (TDOT) to determine the areal extent of the site. Drilling indicated that the fossils occurred in fill material within a paleokarst basin, but the distribution of boreholes does not permit details of sinkhole topography, and therefore its formation and fill history, to be adequately resolved. To better image the sinkhole basin, a high-resolution gravity survey, which included 1104 gravity measurement stations, was conducted. These data were used to create complete Bouguer and residual gravity anomaly maps and a 3D density model via inversionmethods. The residual gravity anomaly map compares favorably with 29 TDOT auger holes drilled to basement, but contains significantly more detail. The residual gravity anomaly map reveals the presence of seven separate sinkholes. However, 3D inverse modeling constrained by drill-hole depths and density data indicates that there are 11 separate sinkholes formed within the Knox Group carbonates. These sinkholes, which range between 20 and [Formula: see text] in depth, are aligned along northwest and northeast trending linear features that correlate to structural features formed during the Appalachian orogenies. It is possible that the overall sinkhole basin formed as the result of partial coalescence of multiple sinkhole structures controlled by a joint system and that the sinkholes then acted as a natural trap for the Gray Fossil Site fauna and flora.
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Miller, William P., Siddharth Sunilkumar, Joseph F. Giordano, Allyson L. Toro, Alistair J. Barber, and Michael D. Dennis. "The stress response protein REDD1 promotes diabetes-induced oxidative stress in the retina by Keap1-independent Nrf2 degradation." Journal of Biological Chemistry 295, no. 21 (April 15, 2020): 7350–61. http://dx.doi.org/10.1074/jbc.ra120.013093.
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The transcription factor nuclear factor erythroid-2–related factor 2 (Nrf2) plays a critical role in reducing oxidative stress by promoting the expression of antioxidant genes. Both individuals with diabetes and preclinical diabetes models exhibit evidence of a defect in retinal Nrf2 activation. We recently demonstrated that increased expression of the stress response protein regulated in development and DNA damage 1 (REDD1) is necessary for the development of oxidative stress in the retina of streptozotocin-induced diabetic mice. In the present study, we tested the hypothesis that REDD1 suppresses the retinal antioxidant response to diabetes by repressing Nrf2 function. We found that REDD1 ablation enhances Nrf2 DNA-binding activity in the retina and that the suppressive effect of diabetes on Nrf2 activity is absent in the retina of REDD1-deficient mice compared with WT. In human MIO-M1 Müller cell cultures, REDD1 deletion prevented oxidative stress in response to hyperglycemic conditions, and this protective effect required Nrf2. REDD1 suppressed Nrf2 stability by promoting its proteasomal degradation independently of Nrf2's interaction with Kelch-like ECH-associated protein 1 (Keap1), but REDD1-mediated Nrf2 degradation required glycogen synthase kinase 3 (GSK3) activity and Ser-351/Ser-356 of Nrf2. Diabetes diminished inhibitory phosphorylation of glycogen synthase kinase 3β (GSK3β) at Ser-9 in the retina of WT mice but not in REDD1-deficient mice. Pharmacological inhibition of GSK3 enhanced Nrf2 activity and prevented oxidative stress in the retina of diabetic mice. The findings support a model wherein hyperglycemia-induced REDD1 blunts the Nrf2 antioxidant response to diabetes by activating GSK3, which, in turn, phosphorylates Nrf2 to promote its degradation.
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Chauvaud, David, and Jean Delfaud. "Use of morphostructural analysis to show halokinesis during Mio-Plio-Quaternary in the South-West part of Aquitain Basin." Bulletin de la Société Géologique de France 173, no. 4 (July 1, 2002): 317–35. http://dx.doi.org/10.2113/173.4.317.
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Abstract In the South Aquitain sector, salt bodies of varying sizes present two geographical gradients. The first gradient, south to north, associated with the proximity of the Pyrenees shows a decreasing deformation of the structures towards the north. The second gradient explains their increasing depth of burial from the west (extrusive structures) to the east (intrusive structures). This organization has been studied from the western sector (Tercis-Bénesse and Bastennes-Louer) to the eastern sector (Viella-Labarthète and Nogaro-Lussagnet). Other more modest structures, revealed by hydrographical anomalies, illustrate halokinetic events during the Quaternary. Then the detailed study of the Geaune dome shows a neotectonic phenomenon dating from the Mio-Pliocene. The radial annular drainage pattern of this structure is guided by recurrent faulting during the Quaternary. Thus the halokinetic dynamics consist in three phases: deformation of the diapirs (overthrusts) during the Oligocene, resuming of halokinesis during the middle of the Miocene and recurrent faulting during the Riss. A model of geomorphological evolution of the domes is then proposed. The first phase (stages of positive relief) is characterized by the centrifugal drainage pattern of the dome. The second phase (stages of inverted relief) is distinguished by the erosion of the center of the structure, by an inversion of the drainage pattern and by the sedimentary accretion in the central depression. Regional frame of the southern-Aquitaine diapirism. – Figure 1 shows the main saliferous bodies. They present a double geographical gradient. The first, S-N, is linked to the Pyrenean tectonics. On the south of the Frontal Overthrust the Trias participated in the overthrusts (St-Jean-de-Pied-de-Port Basin, St-Palais and Salies-de-Béarn structures, etc…). Then in the Outer Sub-Pyrenean zone, the salt forms the axial part of the E-W Pyrenean structures ; finally in the north, in the Aquitaine basin, the diapirs are only slightly deformed. The second gradient, E-W, is linked to the Gulf of Gascogne dynamics where the height of the salt structures decreases from west to east. In Aquitaine, diapirism is a nearly continuous event that has followed the different stages of the history of the basin. The evaporites are deposed in Keuper (Initiation = rifting). The real opening begins in the Albian with the initiation of the turbiditic basins. The main compression begins in the Palaeocene. During the Miocene, the tectonic movements take over with a left lateral transpression on direction N110oE conjugated with recurrent faults N140. Diapirism is reactivated. Certain structures come to the surface. From this rapid historic overview we must retain not only the permanence of diapirism but also the interactive movements between the ascending domes and the subsiding of compensation synclines Evolution of salt structures from West to East. – The cases studied correspond to megastructures (anticlines N140, N090 and multi-kilometric domes) and to the extrusive or intrusive mesostructures (kilometrical domes) which are organized on the ancient Triassic Armorican fault trough. The fact that a E-W global gradient exists for these salt structures is worthnoting: in the eastern sector, the domes are covered with 800 m to 2 000 m of molasse (Lussagnet, Nogaro, Viella-Labarthe, and Geaune) ; coexisting in the western sector are structures of varied forms with an exposed (Tercis, Bénesse, Bastennes) or sub-exposed (Dax) Triassic core. The presence of numerous drainage anomalies (annular and radio-annular drainage patterns) in the east as well as in the west reveals the existence of more modest deep structures. Their morphological expression on the surface shows the continuance of salt deformations during the Quaternary. An exemplary structure: the Geaune salt dome. – It is situated on a trend oriented N060oE. This “ ripple ” has existed since the Upper Jurassic. In fact it concerns an ancient Triassic rift where evaporites accumulated. Afterwards, this Upper Trias deposit underwent a diapiric process which spanned from the Jurassic (middle ? Upper ?) until the present. Geomorphological organization . – The sub-circular structure corresponds both to the valley or dale floor and to flat or convex interfluves. The organization of the drainage shows anomalies characterized by linear and curved structures. Several lineaments in a N140 direction are visible on the eastern half of the dome. They appeared as parallel drains aligned on both sides of the Marcusse brook. Sub-circular structures clearly appear on the sectors A and B of the eroded dome. These curved lineaments are arranged in arcs inside and following the form of the dome. This corresponds to the drainage patterns of the sedimentary domes or exposed diapirs. In the case of the Geaune dome, it concerns a type of complex radio-annular drainage pattern for which the radial drains are largely controlled by the recent fracturing. Dynamics . – Since the Miocene, the history of the Geaune sector has integrated the evolution of the entire gascon piedmont with the deposing of continental sediments (Upper Cenozoic) generating a higher surface followed by, from the Quaternary, the development of the drainage pattern, the formation of present relief and the deposition of alluvial terraces. The diapiric dynamics since Oligocene. – In the Pyrenean foreground, the Oligocene is the paroxysmal phase. The diapiric structures already formed are picked up in the overthrusting ramps (Tercis, Audignon, Riscle). Mio-Pliocene . – In Gascogne, the N140 faults move (in extension ?): they favour a renewal of diapirism which deforms the middle Miocene deposits (Bastennes and Geaune). An inversion with detumescence of the domes then occurs ; the whole is enclosed by the truncation of the higher surface. Quaternary. – The diapir takes over weakly and becomes more pronounced during the Riss. It is associated with toppled boulders orientated N140. The motor is the mobility of the Gulf of Gascogne which participates in the rotation of the Pyrenean rivers towards the west. The inversion occurs at the end of the Riss with a centripetal drainage on the Geaune dome. A type of original model: the inversion ring. – In the northern Pyrenean piedmont, intrusive and extrusive saliferous domes coexist. The analysis of the surface morphostructures which are generated by the rising of these Triassic elements makes the proposal of a detailed model of evolution possible (fig.13). There are five stages regrouped in two phases. In the course of phase I (stage I of positive relief) the drainage is principally centrifugal and radial. During phase II (inversion stages 3, 4 and 5) the center of the dome grows and centripetal radial drains form. The final stage is marked by the filling of the depression. As well as the interest given to the evolution of these structures, the analysis of drainage pattern anomalies and of the forms constitutes an efficient tool of reconnaissance permitting the illustration of, or confirming the presence of deep intrusive saliferous domes.
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Auerswald, K., M. H. O. M. Wittmer, T. T. Männel, Y. F. Bai, R. Schäufele, and H. Schnyder. "Large regional-scale variation in C3/C4 distribution pattern of Inner Mongolia steppe is revealed by grazer wool carbon isotope composition." Biogeosciences 6, no. 5 (May 11, 2009): 795–805. http://dx.doi.org/10.5194/bg-6-795-2009.
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Abstract. This work explored the spatial variation of C3/C4 distribution in the Inner Mongolia, P. R. China, steppe by geostatistical analysis of carbon isotope data of vegetation and sheep wool. Standing community biomass (n=118) and sheep wool (n=146) were sampled in a ~0.2 Mio km2 area. Samples from ten consecutive years (1998–2007) were obtained. Community biomass samples represented the carbon isotopic composition of standing vegetation on about 1000 m2 ("community-scale"), whereas the spatio-temporal scale of wool reflected the isotope composition of the entire area grazed by the herd during a 1-yr period (~5–10 km2, "farm-scale"). Pair wise sampling of wool and vegetation revealed a 13C-enrichment of 2.7±0.7‰ (95% confidence interval) in wool relative to vegetation, but this shift exhibited no apparent relationships with environmental parameters or stocking rate. The proportion of C4 plants in above-ground biomass (PC4, %) was estimated with a two-member mixing model of 13C discrimination by C3 and C4 vegetation (13Δ3 and 13Δ4, respectively), in accounting for the effects of changing 13C in atmospheric CO2 on sample isotope composition, and of altitude and aridity on 13Δ3. PC4 averaged 19%, but the variation was enormous: full-scale (0% to 100%) at community-scale, and 0% to 85% at farm-scale. The farm-scale variation of PC4 exhibited a clear regional pattern over a range of ~250 km. Importantly PC4 was significantly higher above the 22°C isotherm of the warmest month, which was obtained from annual high-resolution maps and averaged over the different sampling years. This is consistent with predictions from C3/C4 crossover temperature of quantum yield or light use efficiency in C3 and C4 plants. Still, temperature gradients accounted for only 10% of the farm-scale variation of PC4, indicating that additional factors control PC4 on this scale.
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Auerswald, K., M. H. O. M. Wittmer, T. T. Männel, Y. F. Bai, R. Schäufele, and H. Schnyder. "Large regional-scale variation in C3/C4 distribution pattern of Inner Mongolia steppe is revealed by grazer wool carbon isotope composition." Biogeosciences Discussions 6, no. 1 (January 12, 2009): 545–74. http://dx.doi.org/10.5194/bgd-6-545-2009.
Full textAbstract:
Abstract. This work explored the spatial variation of C3/C4 distribution in the Inner Mongolia, China, steppe by geostatistical analysis of carbon isotope data of vegetation and sheep wool. Standing community biomass (n=118) and sheep wool (n=146) were sampled in a ~0.2 Mio km2 area. Samples from ten consecutive years (1998–2007) were obtained. Community biomass samples represented the carbon isotopic composition of standing vegetation on about 1000 m2 ("community-scale"), whereas the spatio-temporal scale of wool reflected the isotope composition of the entire area grazed by the herd during a 1-yr period (~5–10 km2, "farm-scale"). Pair wise sampling of wool and vegetation revealed a 13C-enrichment of 2.7‰ in wool relative to vegetation, but this shift exhibited no apparent relationships with environmental parameters or stocking rate. The proportion of C4 plants in above-ground biomass (PC4, %) was estimated with a two-member mixing model of C3 and C4 13C discrimination (13Δ3 and 13Δ4, respectively), in accounting for the effects of changing 13C in atmospheric CO2 on sample isotope composition, and of altitude and aridity on 13Δ3. PC4 averaged 19%, but the variation was enormous: full-scale (0% to 100%) at community-scale, and 0% to 85% at farm-scale. The farm-scale variation of PC4 exhibited a clear regional pattern over a range of ~250 km. Importantly PC4 was significantly higher above and lower below the 22°C isotherm of the warmest month, which was averaged from high-resolution maps of the sample years. This is consistent with predictions from C3/C4 crossover temperature of quantum yield in C3 and C4 plants. Still, temperature gradients accounted for only 10% of the farm-scale variation of PC4, indicating that additional factors control PC4 on this scale.
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Godard, Vincent, Jean-Claude Hippolyte, Edward Cushing, Nicolas Espurt, Jules Fleury, Olivier Bellier, and Vincent Ollivier. "Hillslope denudation and morphologic response to a rock uplift gradient." Earth Surface Dynamics 8, no. 2 (April 7, 2020): 221–43. http://dx.doi.org/10.5194/esurf-8-221-2020.
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Abstract. Documenting the spatial variability of tectonic processes from topography is routinely undertaken through the analysis of river profiles, since a direct relationship between fluvial gradient and rock uplift has been identified by incision models. Similarly, theoretical formulations of hillslope profiles predict a strong dependence on their base-level lowering rate, which in most situations is set by channel incision. However, the reduced sensitivity of near-threshold hillslopes and the limited availability of high-resolution topographic data has often been a major limitation for their use to investigate tectonic gradients. Here we combined high-resolution analysis of hillslope morphology and cosmogenic-nuclide-derived denudation rates to unravel the distribution of rock uplift across a blind thrust system at the southwestern Alpine front in France. Our study is located in the Mio-Pliocene Valensole molassic basin, where a series of folds and thrusts has deformed a plateau surface. We focused on a series of catchments aligned perpendicular to the main structures. Using a 1 m lidar digital terrain model, we extracted hillslope topographic properties such as hilltop curvature CHT and nondimensional erosion rates E∗. We observed systematic variation of these metrics coincident with the location of a major underlying thrust system identified by seismic surveys. Using a simple deformation model, the inversion of the E∗ pattern allows us to propose a location and dip for a blind thrust, which are consistent with available geological and geophysical data. We also sampled clasts from eroding conglomerates at several hilltop locations for 10Be and 26Al concentration measurements. Calculated hilltop denudation rates range from 40 to 120 mm kyr−1. These denudation rates appear to be correlated with E∗ and CHT that were extracted from the morphological analysis, and these rates are used to derive absolute estimates for the fault slip rate. This high-resolution hillslope analysis allows us to resolve short-wavelength variations in rock uplift that would not be possible to unravel using commonly used channel-profile-based methods. Our joint analysis of topography and geochronological data supports the interpretation of active thrusting at the southwestern Alpine front, and such approaches may bring crucial complementary constraints to morphotectonic analysis for the study of slowly slipping faults.
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Marx, Axel, and Adrian Dusa. "Crisp-Set Qualitative Comparative Analysis (csQCA), Contradictions and Consistency Benchmarks for Model Specification." Methodological Innovations Online 6, no. 2 (August 2011): 103–48. http://dx.doi.org/10.4256/mio.2010.0037.
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Sukumar, Madhusudhanan, Andrea Wilke, Josef Mautner, Hans-Jochem Kolb, Georg Bornkamm, and Armin Gerbitz. "Rejection of Primary Lymphoma Cells Derived from c-myc-Transgenic Mice after Haploidentical Transplantation: Treatment of the Tumor May Confer to Resistance Against GvL-Effect." Blood 106, no. 11 (November 16, 2005): 5243. http://dx.doi.org/10.1182/blood.v106.11.5243.5243.
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Abstract The long term prognosis of the High Grade B-cell-lymphoma in adults is still very poor, especially in the case of resistance to chemotherapy. To date allogeneic stem cell transplantation as a last treatment option results in poor outcomes due to high transplant related mortality or disease progression. This dilemma raises the question of whether transplant related mortality could be reduced by earlier transplantation, and whether such tumors can be recognized by an allogeneic graft providing a graft versus lymphoma effect. The immunology behind allogeneic rejection of high grade lymphomas is poorly understood due to a dearth of good animal models. Using a transgenic mouse model in which the human c-myc oncogene is driven by the human immunoglobuline lambda locus mimicking a t(8;22) translocation of Burkitt’s lymphoma, we established primary lymphoma cell lines. C57BL/6c-myc tg mice were crossbred with DBA mice and lymph nodes from tumor bearing F1-mice were explanted and seeded on irradiated human MRC5 fibroblast feeder cells. Approximately 70% of all explanted lymphomas established long term cultures which could be maintained free of feeder cells after 4 to 6 weeks. FACS analysis of lymphoma cells displayed strong CD19 expression, reduced expression of MHC Class I and II and, in several cases, low expression of costimulatory molecules such as CD80, CD86 and CD54. The phenotype was maintained over time with a follow up of up to 4 months. As few as 100 lymphoma cells gave rise to orthotopic tumors or systemic disease within 40 days after s.c. or i.v. injection, respectively. On the contrary, when 50 Mio. F1-lymphoma cells were injected into haploidentical C57BL6 parental animals, no tumor growth could be observed after at least 100 days of follow up. Despite fast growth and low expression of MHC Class I and costimulatory molecules, lymphoma cells were easily rejected in a haploidentical setting. Ex vivo chemotherapy treatment of lymphoma cells resulted in resistance after 2 courses of 100nM Adriamycine. Increased doses up to 500nM Adriamycine further accelerated resistance and growth speed of the cells. Flow cytometric analysis indicated a reduced fraction of apoptotic cells in culture suggesting selection for cells bearing alteration in the apoptotic pathways. In further experiments altered cells will be tested in haploidentical settings to confirm clinical experience in our model.
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Lehmann, Frank, Armin Gerbitz, Christoph Loddenkemper, Elisabeth Kremmer, Josef Mautner, Thomas Kammertöns, and Georg Bornkamm. "CD19 as Foreign Antigen Elicits a Specific T-Cell Response and Mediates Rejection of High Grade B-Cell Lymphoma In Mice." Blood 116, no. 21 (November 19, 2010): 4907. http://dx.doi.org/10.1182/blood.v116.21.4907.4907.
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Abstract Abstract 4907 Targeting selfantigens by specific T-cells for anti-tumor therapy bears the risk of fatal autoimmunity. Ideal self antigens are characterized by restricted expression in a specific cell compartment and are ideally highly expressed in malignant cells. Potential autoimmunity against those antigens must be tolerable for the host and loss of the expressing cell compartment has to be acceptable. In addition such self antigens should deliver survival signals for the tumor making escape variants highly unlikely or even impossible. The CD19 molecule as a member of the Ig superfamily is a transmembrane protein whose expression is restricted to B-cells in mouse and man. Aside from other proteins (CD81, CD21 etc.) it associates with the B-cell receptor (BCR) to augment its signal and appears to be of critical importance in the development and differentiation of B-cells. CD19 is expressed on virtually all B-cell malignancies and may provide a survival signal for at least some B cell malignancies. Targeting CD19 by antibodies appears to be effective in disease control making it an interesting target for T-cell therapy. We have developed a murine model for high grade B-cell lymphoma using lambda-human-cmyc transgenic mice. These animals spontaneously develop high grade B-cell lymphomas with similarities to human Burkittxs lymphoma. From these mice we established various cell lines which can be cultured long term and transferred onto recipients to form new locally or systemically growing lymphomas. Using homozygous CD19cre mice as a model for CD19 deficiency we show here that transfer of lethal doses of lymphoma cells (0.1-1.0 Mio 291cells) which form lymphomas in more than 90% of wild type recipients can be rejected long term (100 days) in up to 60% (9/14) of CD19 deficient mice (p=0.001, left figure). After s.c. injection 9/14 of CD19-/- animals transiently form tumors at the site of injection (right figure CD19-/-B6 rejection) which eventually disappear as a sign of rejection. STAT1-/- deficient animals served as a positive control since they harbour a NK- and T-cell defect. In case of outgrowing tumors (5/14), we still observe a strong infiltration by T-cells which is completely absent in wild type recipients. Heterotypic prime-boost-vaccination of CD19 deficient mice using a CD19 expression vector and long peptides results in a strong T-cell response as shown by IFNgamma ELISPOT and ELISA assay which is absent in wt mice or control vaccinated animals (chicken ovalbumine, OVA). Using peptide prediction several epitopes within the murine CD19 protein could be identified giving rise to mainly CD4 responses in the context of MHC H2b. Vaccination of CD19 deficient animals is being done to further improve survival of tumor-challenged animals. Collectively, our data indicate that CD19 serves as a rejection antigen in our model system and that protective T-cell responses can be generated to provide long survival after tumor challenge. Disclosures: No relevant conflicts of interest to declare.
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Pownall, J. M., R. Hall, and I. M. Watkinson. "Extreme extension across Seram and Ambon, eastern Indonesia: evidence for Banda slab rollback." Solid Earth 4, no. 2 (September 24, 2013): 277–314. http://dx.doi.org/10.5194/se-4-277-2013.
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Abstract. The island of Seram, which lies in the northern part of the 180°-curved Banda Arc, has previously been interpreted as a fold-and-thrust belt formed during arc-continent collision, which incorporates ophiolites intruded by granites thought to have been produced by anatexis within a metamorphic sole. However, new geological mapping and a re-examination of the field relations cause us to question this model. We instead propose that there is evidence for recent and rapid N–S extension that has caused the high-temperature exhumation of lherzolites beneath low-angle lithospheric detachment faults that induced high-temperature metamorphism and melting in overlying crustal rocks. These "Kobipoto Complex" migmatites include highly residual Al–Mg-rich garnet + cordierite + sillimanite + spinel + corundum granulites (exposed in the Kobipoto Mountains) which contain coexisting spinel + quartz, indicating that peak metamorphic temperatures likely approached 900 °C. Associated with these residual granulites are voluminous Mio-Pliocene granitic diatexites, or "cordierite granites", which crop out on Ambon, western Seram, and in the Kobipoto Mountains and incorporate abundant schlieren of spinel- and sillimanite-bearing residuum. Quaternary "ambonites" (cordierite + garnet dacites) emplaced on Ambon were also evidently sourced from the Kobipoto Complex migmatites as demonstrated by granulite-inherited xenoliths. Exhumation of the hot peridotites and granulite-facies Kobipoto Complex migmatites to shallower structural levels caused greenschist- to lower-amphibolite facies metapelites and amphibolites of the Tehoru Formation to be overprinted by sillimanite-grade metamorphism, migmatisation, and limited localised anatexis to form the Taunusa Complex. The extreme extension required to have driven Kobipoto Complex exhumation evidently occurred throughout Seram and along much of the northern Banda Arc. The lherzolites must have been juxtaposed against the crust at typical lithospheric mantle temperatures in order to account for such high-temperature metamorphism and therefore could not have been part of a cooled ophiolite. In central Seram, lenses of peridotites are incorporated with a major left-lateral strike-slip shear zone (the "Kawa Shear Zone"), demonstrating that strike-slip motions likely initiated shortly after the mantle had been partly exhumed by detachment faulting and that the main strike-slip faults may themselves be reactivated and steepened low-angle detachments. The geodynamic driver for mantle exhumation along the detachment faults and strike-slip faulting in central Seram is very likely the same; we interpret the extreme extension to be the result of eastward slab rollback into the Banda Embayment as outlined by the latest plate reconstructions for Banda Arc evolution.
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Ito, Mio. "Construction of depopulated area model of communication about dementia care." Impact 2020, no. 9 (December 30, 2020): 40–42. http://dx.doi.org/10.21820/23987073.2020.9.40.
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In Japan there are remote villages, mountainous areas and islands where the population includes people who are extremely old. Owing to the remoteness of these places, there are very few long-term care insurance services and medical institutions meaning that the residents often have no choice but to support each other. This situation is particularly problematic for people with dementia. Caring for dementia patients requires specialised knowledge which is often beyond the residents of depopulated areas in Japan. It is with this in mind that Associate Professor Mio Ito has joined forces with Dr Chiho Shimada and Dr Ryo Hirayama to improve care and communication for persons with dementia in depopulated areas.
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Pownall, J. M., R. Hall, and I. M. Watkinson. "Extreme extension across Seram and Ambon, eastern Indonesia: Evidence for Banda slab rollback." Solid Earth Discussions 5, no. 1 (April 17, 2013): 525–607. http://dx.doi.org/10.5194/sed-5-525-2013.
Full textAbstract:
Abstract. The island of Seram, which lies in the northern part of the 180°-curved Banda Arc, has previously been interpreted as a fold-and-thrust belt formed during arc-continent collision, which incorporates ophiolites intruded by granites thought to have been produced by anatexis within a metamorphic "sole". However, new geological mapping and a re-examination of the field relations cause us to question this model. We instead propose that there is evidence for recent N–S extension that has caused the high-temperature exhumation of hot mantle peridotites, granites, and granulites (the "Kobipoto Complex") beneath low-angle lithospheric detachment faults. Greenschist- to lower-amphibolite facies metapelites and amphibolites of the Tehoru Formation, which comprise the hanging wall above the detachment faults, were overprinted by sillimanite-grade metamorphism, migmatisation and limited localised diatexis to form the Taunusa Complex. Highly aluminous metapelitic garnet + cordierite + sillimanite + spinel + corundum + quartz granulites exposed in the Kobipoto Mountains (central Seram) are intimately associated with the peridotites. Spinel + quartz inclusions in garnet, which indicate that peak metamorphic temperatures for the granulites likely approached 900 °C, confirm that peridotite was juxtaposed against the crust at typical lithospheric mantle temperatures and could not have been part of a cooled ophiolite. Some granulites experienced slight metatexis, but the majority underwent more advanced in situ anatexis to produce widespread granitic diatexites characterised by abundant cordierite and garnet xenocrysts and numerous restitic sillimanite + spinel "clots". These Mio-Pliocene "cordierite granites", which are present throughout Ambon, western Seram, and the Kobipoto Mountains in direct association with peridotites, demonstrate that the extreme extension required to have driven Kobipoto Complex exhumation must have occurred along much of the northern Banda Arc. In central Seram, smeared lenses of peridotites are incorporated with a major left-lateral strike-slip shear zone (the "Kawa Shear Zone"), demonstrating that strike-slip motions likely initiated shortly after the mantle had been partly exhumed by detachment faulting and that the main strike-slip faults may themselves be reactivated and steepened low-angle detachments. The Kobipoto Mountains represent a left-lateral pop-up structure that has facilitated the final stages of exhumation of the high-grade Kobipoto Complex through overlying Mesozoic sedimentary rocks. On Ambon, Quaternary "ambonites" (cordierite + garnet dacites) are evidently the volcanic equivalent of the cordierite granites as they also contain granulite-inherited xenoliths and xenocrysts. The geodynamic driver for mantle exhumation along the detachment faults and strike-slip faulting in central Seram is very likely the same – we interpret the extreme extension to be the result of eastward slab rollback into the Banda Embayment as outlined by the latest plate reconstructions for Banda Arc evolution.
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Poisson, André, Fabienne Orszag-Sperber, Erdal Kosun, Maria-Angella Bassetti, Carla Müller, Roland Wernli, and Jean-Marie Rouchy. "The Late Cenozoic evolution of the Aksu basin (Isparta Angle; SW Turkey). New insights." Bulletin de la Société Géologique de France 182, no. 2 (March 1, 2011): 133–48. http://dx.doi.org/10.2113/gssgfbull.182.2.133.
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Abstract The Mio-Pliocene basins around the Antalya gulf in SW Turkey developed above the Tauric Mesozoic platforms on which the Antalya nappes had been thrusted (in Late Cretaceous-Paleocene times). The closure of the initial Isparta Angle during these events (E-W compression) initiated the N-S orientation of the main structural lines, which persisted later and explains the orientation of the Aksu basin in contrast with the E-W orientation of the eastern Neo-gene Mediterranean basins. The area, and all southwestern Turkey, became emergent at the end of the Oligocene and were the site of shallow-marine carbonate deposits in the Chattian-Aquitanian, giving way to the wide Lycian basin in Burdigalian-Langhian times. The progressive emplacement of the Lycian nappes from the north over this basin provoked first its subsidence and then its emersion when the nappes attained their final position over the Bey Daglari platform in Langhian times. Coinciding, or in response to the Lycian nappes emplacement, the Aksu basin was initiated as an elongated N-S graben which was filled by thick accumulations of terrestrial and marine deposits(including coral reefs), which derived from the erosion of the Lycian allochton and its basement (Langhian?, Serravallian and Tortonian times). The syn-sedimentary tectonics : reactivation of the normal faults along the west margin of the basin, the continuous uplift of the neighbouring continental areas (beginning of the Aksu thrust), governed the geometry of the basin. As a result and due to the uplift of its northern margin, the Aksu basin migrated towards the south and in Messinian times it was reduced to a narrow gulf along the eastern margin of which the Gebiz limestones were deposited as fringing coral reefs. The age of these limestones has been debated. Our new data allow us to attribute them to the Messinian. The drastic retreat of the sea at the end of this period, provoked the erosion of large parts of the Messinian deposits and the formation of deep canyons on land and under the sea down to the Antalya abyssal plain, in which evaporites were deposited. During the Zanclean transgression, the Eskiköy-Kargi canyon was filled by coarse clastics of a Gilbert delta derived from the northern continental area following a model well known elsewhere in the Mediterranean basins. Southward, shallow-marine sands and marls unconformably cover the remnants of the Messinian deposits and the emergent areas of the southern Antalya gulf. After Zanclean times (end of Pliocene?), the Aksu basin was deformed, due to the west-directed Aksu compressional event (end of the Aksu thrust). Quaternary terraces of the Aksu river at various altitudes, as well as the terraces of the Antalya tufa can be related to sea level fluctuations.
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Helm, Florian, Andrea Wilke, Thomas Kammertoens, Christian Friese, Josef Mautner, Christoph Loddenkemper, Georg Bornkamm, and Armin Gerbitz. "Immunisation against Human c-MYC Elicits a T-Cell Response and Influences Growth of High Grade B-Cell Lymphoma in Mice." Blood 114, no. 22 (November 20, 2009): 5120. http://dx.doi.org/10.1182/blood.v114.22.5120.5120.
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Abstract Abstract 5120 Overexpression of the proto-oncogene c-myc due to chromosomal translocation is the hallmark of Burkitt-lymphoma. The evolving high grade lymphoma is dependent on the overexpression of c-myc, which provides the necessary signal to drive uncontrolled proliferation. Therefore loss of function or recognition of c-myc overexpressing cells by c-MYC specific T-cells should result in killing of the target and a halt to lymphoma progression. C-myc is also expressed in a variety of other human malignancies. Peptide prediction reveals several potential foreign epitopes in the context of murine H2b due to 87% homology between human and mouse c-MYC. In this study we explored whether the human c-myc gene product can be a target for T-cell therapy. Wildtype C57BL/6 mice were immunized with recombinant human c-MYC protein in combination with incomplete Freund′s adjuvans and CpG, and were boosted at various time points thereafter using either c-MYC protein or 40mer peptides encompassing the non homologous regions. Control animals were vaccinated with recombinant GFP or OVA protein. C-MYC vaccinated animals displayed a higher IFNg release upon re-stimulation with c-MYC pulsed dendritic cells compared to control vaccinated animals. In ELISPOT assays we observed a higher number of IFNg positive cells (299±17 vs. 122±8.5 (GFP vaccinated) vs. 66±8.5 (OVA vaccinated)). Vaccination using single peptides revealed that peptides spanning the region from amino acid 87-123, 216-255 and 334-376 produced similar results. In addition, using a human c-MYC specific ELISA we were able to detect c-MYC specific antibodies in serum from immunized mice in a concentration up to 40mg/l. Using established cell lines from l-hu-c-myc transgenic mice, where the human c-myc gene is overexpressed due to the juxtaposition of elements of the immunoglobuline lambda locus as found in t(8;22) of Burkitt's lymphoma, we investigated whether vaccination with human c-MYC protein would influence lymphoma growth in a lymphoma transfer model. Animals were s.c. challenged with 0.1 Mio 291cells overexpressing human c-MYC and were monitored for lymphoma growth. C-MYC vaccinated animals (n=15) displayed a delay in tumor onset and a significantly better disease free survival (28 vs. 22 days, p=0.012) compared to control (OVA) vaccinated animals (n=10). This delayed growth was associated with an increased number of infiltrating CD3+/Perforin+ cells. However, all mice eventually succumbed to lymphoma growth, indicating that the T-cell response was not sufficient to control lymphoma growth in the long term. From these data we conclude that the human c-MYC is a possible target antigen for T-cells, but responses are weak and presumably low in frequency. Disclosures No relevant conflicts of interest to declare.
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Gerbitz, Armin, Madhusudhanan Sukumar, Florian Helm, Andrea Wilke, Christian Friese, Cornelia Fahrenwaldt, Frank Lehmann, et al. "Stromal Cross-Presentation and Host Interferon-γ Signaling and Are Required for Elimination of Antigen-Loss Variants of High-Grade B Cell Lymphomas: Implications for Adoptive T Cell Therapy." Blood 116, no. 21 (November 19, 2010): 3927. http://dx.doi.org/10.1182/blood.v116.21.3927.3927.
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Abstract Abstract 3927 The incidence of high-grade B cell lymphomas has been increasing over the last decades in western countries for unclear reasons. Relapse after conventional chemotherapy especially in high-grade B cell lymphomas remains a very difficult clinical issue. Contrary to CML and AML, the benefit of allogeneic SCT for treatment of high-grade lymphomas is not well established. Several studies suggested a potential graft versus lymphoma (GvL) effect for acute lymphoblastic leukemia (ALL) and several types of non-Hodgkin lymphomas. To study mechanisms involved in T cell-mediated rejection of B cell lymphomas, we have developed a murine lymphoma model in which three antigens, human c-MYC protein, chicken ovalbumin (OVA) and GFP, serve as foreign antigens for rejection. Lymphomas expressing all three antigens were rejected in 60 to 70% of animals after transfer into wild type mice, whereas lymphomas expressing only human c-MYC protein were not rejected. Outgrowing OVA-expressing lymphomas were infiltrated by T cells, showed MHC class I and II upregulation and loss of antigen expression, indicating immune escape. In contrast to wild type recipients of OVA-expressing lymphomas, 80 to 100% of recipient STAT1-, IFN-γ-, or IFN-γ receptor-deficient mice died due to lymphoma growth. Remarkably, lymphomas arising in IFN-γ- and IFN-γ-receptor-deficient mice also invariably showed lost antigen expression. Thus, poor overall survival of IFN-γ- and IFN-γ-receptor-deficient recipient mice is not due to a lack of antigen-specific T cell killing but due to inefficient eradication of antigen-negative variants of the lymphoma. In order to address the role of the stroma in eradication of lymphoma cells we made use of B6bm1 animals that do not present the immunodominant OVA derived peptide SIINFEKL in the context of MHC class I. Since the wildtype MHC represents an allo-antigen in B6bm1 mice, B6bm1 and B6 wildtype control recipients were T-cell depleted by 30H12 anti CD90.2 antibody prior to transfer of lymphoma cells. Anti OVA immunity was restored by adoptive transfer of 1 Mio. primed CD90.1+ OT-I-T-cells one day after lymphoma transfer. T-cell depletion was continued for 28 days biweekly. Lymphoma growth was faster in bm1 recipients and disease free survival significantly reduced (A). In addition, T-cell expansion was significantly reduced (B) in bm1 recipients as analyzed by pentamer staining of OT-I-T-cells in peripheral blood (day 21 0.84%±0.2 vs. 3.53%±0.2 of lymphocytes, p=0.001) indicating an important role of stromal crosspresentation for the rejection of lymphoma cells. Our data show that mechanisms established for solid tumors hold true also for hematologic neoplasias such as B cell lymphomas. Antigen-dependent eradication of tumor antigen-loss variants makes antigen-specific T cell therapy particularly attractive as a novel therapeutic treatment option. Disclosures: No relevant conflicts of interest to declare.
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Herter, Sylvia, Inja Waldhauer, Tina Otz, Frank Herting, Sabine Lang, Valeria Nicolini, Michaela Römmele, et al. "Superior Efficacy of the Novel Type II, Glycoengineered CD20 Antibody GA101vs. the Type I CD20 Antibodies Rituximab and Ofatumumab." Blood 116, no. 21 (November 19, 2010): 3925. http://dx.doi.org/10.1182/blood.v116.21.3925.3925.
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Abstract Abstract 3925 GA101 is Type II, glycoengineered CD20 monoclonal antibody currently in PhII/III clinical trials. We have previously shown that GA101 mediates superior in vitro and in vivo activity compared to the Type I CD20 antibody rituximab. By epitope mapping and crystallography we have shown that GA101 recognizes CD20 in a unique way that is different from Type I CD20 antibodies and have proposed that this may be the basis for the Type II character of GA101. Here we compare for the first time GA101 with rituximab, the standard of care in various clinical settings in NHL and B-CLL in combination with chemotherapy, as well as with the Type I CD20 antibody ofatumumab, which was recently approved for treatment of B-CLL patients refractory to fludarabine and alemtuzumab. The following assays were used to compare the three anti-CD20 antibodies: i) Binding to NHL cell lines Z138 (MCL, ca. 60.000 CD20 binding sites per cell) and SU-DHL4 (DLBCL, ca. 1 Mio CD20 binding sites per cell) assessed by FACS, ii) Cell death induction, detected by AxV/PI staining and FACS, on a panel of NHL cell lines, iii) Antibody dependent cellular cytotoxicity mediated by PBMNCs as effector and Z138, SU-DHL4 as target cells (ADCC, LDH release assay); iv) Complement dependent cytotoxicity with Z138, SU-DHL4 as target cells (CDC, LDH release assay) and v) B-cell depletion (assessed by FACS) in whole blood from healthy donors. Dose-dependent anti-tumoral activity was assessed in a s.c. SU-DHL4 NHL xenograft model in Scid beige mice. Survival experiments in a disseminated Z138 MCL model are ongoing and an update on the results will be included as part of the poster presentation. Ofatumumab (“Arzerra”) was purchased from a local pharmacy, GA101 and rituximab were obtained from Hoffmann La Roche AG, Basel. First, binding studies confirmed that GA101 shows half-maximal binding to NHL cells relative to rituximab and ofatumumab, a known property of Type II CD20 antibodies. EC50 values of binding were comparable indicating that GA101, rituximab and ofatumumab have apparent binding affinities in the low nanomolar range on NHL cells independent of the level of CD20 expression. Second, the three CD20 antibodies were compared for their induction of direct cell death as measured by AxV/PI staining. Overall, GA101 mediated superior direct cell death induction compared to rituximab and ofatumumab utilizing a panel of NHL cell lines of different origins. Immune effector-related mechanisms of action were subsequently compared by ADCC and CDC assays. GA101, a glycoengineered antibody with enhanced affinity for FcgRIIIa, was found to exhibit up to 100-fold higher ADCC potency than rituximab and ofatumumab on Z138 and SU-DHL4 cells. CDC, as expected for a Type II CD20 antibody was ca. 10 to 1,000 less potent compared to the Type I antibodies rituximab and ofatumumab. In order to integrate the different mechanisms of action (direct cell death, ADCC, CDC), autologous ex vivo B-cell depletion assays with whole blood from healthy donors containing natural immune effector cells, human complement and physiological concentrations of human immunoglobulins were performed. These studies showed that GA101 was more potent in terms of EC50 values and more efficacious in terms of absolute B-cell depletion when compared to rituximab and ofatumumab. Finally, the dose-dependent effects of the three CD20 antibodies was studied on the growth of s.c. SU-DHL4 DLBCL xenografts in SCID beige mice. GA101 induced a dose-dependent anti-tumoral effect including complete tumor remission and was superior to the Type I antibodies rituximab and ofatumumab at saturating antibody doses. In summary, the preclinical data presented herein demonstrate that the Type II, glycoengineered CD20 antibody GA101 is differentiated from the Type I CD20 antibodies rituximab and ofatumumab by its superior overall activity supporting its further clinical investigation. Of note, in contrast to previous publications, in this series of assays no superior preclinical activity of ofatumumab was observed when compared to rituximab. Disclosures: Herter: Roche: Employment, Patents & Royalties. Waldhauer:Roche: Employment. Otz:Roche: Employment. Herting:Roche: Employment, Patents & Royalties. Lang:Roche: Employment. Nicolini:Roche: Employment. Römmele:Roche: Employment. Friess:Roche: Employment, Patents & Royalties. Van Puijenbroek:Roche: Employment. Bacac:Roche: Employment. Weidner:Roche: Employment, Equity Ownership. Gerdes:Roche: Employment, Equity Ownership, Patents & Royalties. Umana:Roche: Employment, Equity Ownership, Patents & Royalties. Klein:Roche: Employment, Equity Ownership, Patents & Royalties.
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Guarracino, Serena. "«Come muovermi nel mio corpo da uomo»: il corpo maschile travestito nel teatro inglese, dai ragazzi attori a Caryl Churchill." Storia delle Donne 16 (July 7, 2021): 37–53. http://dx.doi.org/10.36253/sd-11461.
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Among the many traditions of cross-dressing in performing practices, English Renaissance theatre plays a central symbolic role, especially considering the Shakespearean canon; however, only through the disruptive reading of gender and queer studies Shakespeare’s theatre has been studied as a transvestite theatre in which all female parts were played by boy actors. This article intends to show how this transvestite body opens a diachronic perspective on those theatrical practices of the second half of the twentieth century that rediscover the Elizabethan stage as a locus of artifice. Renaissance and twentieth-century theatre thus share the transvestite male body, not following a linear dynamic of model and imitation, but in a much more complex interweaving of echoes and returns. Through an analysis of two works by the playwright Caryl Churchill, Cloud Nine (1979) and A Mouthful of Birds (1986), the essay explores the transvestite male body as a place of dialogue between the Shakespearean and the contemporary scene, which share effeminacy -here understood as the staging of femininity on a male body- as a detonator for a wider crisis of binary categories.
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Bigot-Cormier, Florence, Françoise Sage, Marc Sosson, Jacques Déverchère, Michelle Ferrandini, Pol Guennoc, Michel Popoff, and Jean-François Stéphan. "Pliocene deformation of the north-Ligurian margin (France) : consequences of a south-Alpine crustal thrust." Bulletin de la Société Géologique de France 175, no. 2 (March 1, 2004): 197–211. http://dx.doi.org/10.2113/175.2.197.
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Abstract Introduction.– The Oligo-Miocene extension phase of the Mediterranean basins rifting (30–25 Ma) [Jolivet and Faccenna, 2000] followed by the Ligurian basin oceanic crust formation (21–18 Ma) [Le Pichon et al., 1971 ; Réhault et al., 1984 ; Carminati et al., 1998 ; Gueguen et al., 1998] occurred during the western Alps compression phase. The deformations were characterised during the Miocene by the southwestward structuration of the Castellane Arc [Fallot and Faure-Muret, 1949 ; Laurent et al., 2000] and during the Mio-Pliocene by the southward structuration of the Nice Arc. This latter arc is bounded on its western side by a dextral strike-slip fault and on its southern side by a thrust inducing an uplift of this arc [Ritz, 1991 ; Guglielmi and Dubar, 1993 ; Clauzon et al., 1996 ; Guardia et al., 1996 ; Schroetter, 1998]. Fission tracks thermochronology data [Bigot-Cormier et al., 2000] suggest a general uplift at ~3.5 Ma of the Argentera massif. Stratigraphical [Irr, 1984 ; Hilgen, 1991 ; Hilgen and Langereis, 1988, 1993] and geomorphological studies [Clauzon et al., 1996 b ; Dubar and Guglielmi, 1997] show evidences for an uplift of the Ligurian coast increasing east of the Var river. The analysis of 70 seismic-reflection profiles allows us to better characterise and quantify the deformation from Antibes to Imperia (fig. 1). We then reconstruct vertical motions in space and time since the Messinian crisis in order to propose a deformation model of the margin related to crustal thickening. Morpho-structural and sedimentary characteristics of the margin. – The morphology of the margin results both from the Oligocene rifting and the Messinian crisis (5.8–5.3 Ma) characterised by a sea level fall of ~1500 m. At the surface, the margin, with a steep mean slope of 6–8o near Antibes [Réhault, 1981] to 12o near Imperia [Savoye and Piper, 1991], is cut by several canyons. At depth, there are two or three tilted blocks covered by Mesozoic sediments and in the Imperia area by the Helminthoïd Flyschs [Sosson et al., 1998]. In the basin, above the Miocene units, we observe some lower evaporites at the bottom, the Messinian salt in the middle and upper evaporites (E) marking the end of the low sea level 5.32 Ma ago [Ryan et al., 1973 ; Mauffret et al., 1973 ; Réhault 1981 ; Savoye and Piper, 1991]. The sedimentary series ends with 1500 m thick of Plio-Quaternary units [Gennesseaux and Le Calvez, 1960 ; Sosson et al., 1998]. At the top of the margin, we observe an erosion surface while toward the basin, two units are evidenced : the Messinian fan (CYL 30–05, fig. 2) unconformity, covered by a seismic facies similar to the one of the upper evaporites in the basin. The “M” surface, that relates the erosional surface of the margin and the upper evaporites of the basin, has a regular slope toward the basin (fig. 3). We will use this surface as a stratigraphic and structural reference for this work. Acquisition and methodology. – We analysed 12 profiles from the MALIGU cruise (1993–1994) [Chaumillon et al., 1994] and ~ 60 from several cruises (1992–2001) with the “Tethys” oceanographic ship to synthesize all stratigraphic and structural observations along the margin. In this paper, we only present 12 of them. We quantify the deformation at the margin/basin limit with a velocity gradient [Le Douaran et al., 1984 ; Rollet, 1999 ; Contrucci et al., 2001] on 50 profiles and we propose a deformation chronology using the “M” surface. Evidence for Pliocene deformation – Between Antibes and the east of Nice : there is no deformation of the “M” surface (fig. 3). – Between the east of Nice and the west of Menton : we observe a deformation at the top of the margin characterised by tilted seismic reflectors (fig. 4A). According to the micro-paleontology study, this deformation is dated at the Lower-Upper Pliocene limit. – From the west of Menton to San Remo : the deformation, observed in the middle of the margin, is characterised by a tilted Messinian fan and the formation of small basins (fig. 4A,B). We note that this deformation increases when the margin strikes ENE-WSW. – From San Remo to Imperia : the deformation increases from the middle to the base of the margin (fig. 4B). The apparent normal throw estimated at ~ 500 m near Antibes increases up to more than 2000 m near Imperia since ~ 5 Ma (fig. 5). This deformation induced (i) the formation of a piggy-back basin located near Imperia, (ii) a decrease of the “M” surface slope with at places a slope inversion compared with the Antibes area (fig. 4B). Space and time reconstitution of vertical motions. – In order to better visualise the geometry of the structure of the margin, we drew seismic profiles with no exaggeration. We interpret the observations seen above and the fact that normal faults on the rifted tilted blocks show a slope between 45–30o as the occurrence of a blind thrust (fig. 6). Motion along the thrusting plane induces the rotation of tilted blocks and is responsible for the margin uplift during the Lower-Upper Pliocene limit following a book-shelf mechanism [Mandl, 1987 ; Jackson and McKenzie, 1983]. At the bottom of the margin, we therefore interpret the apparent normal fault as a gravitary sliding (fig. 7) which enhances the front of the thrust vanishing in the Messinian salt unit. Discussion – Comparison between this model and others previously proposed : contrary to the model proposed by Chaumillon et al. [1994], we can explain the uplift of the margin and the presence of the “normal” faults at the limit margin/basin, only with one mechanism of crustal compression. This mechanism clearly comes from onshore and not from offshore as suggested by Béthoux et al. [1992]. The thrust, dipping toward the continent, can be observed on multichanel seismic reflection profiles [Rollet, 1999] (fig. 8). – The compression of the margin since the end of the lower-Pliocene : our results are chronologically and geometrically in agreement with reversal faults dipping toward the continent, observed along Cap Mele (fig. 1) at the bottom of the Pliocene units [Réhault, 1981]. Both, the important thickness of the Plio-Quaternary sediments near Imperia, far away from the Var river, and the many salt diapirs in the NE area, are consistent with a thrust motion. – The area Argentera massif-Ligurian margin : according to fission track data [Bigot-Cormier et al., 2000] a major uplift was detected at ~3.5 Ma. At the same time, the Ligurian margin recorded a compressive phase with a structural geometry consistent with the deformation onshore (fig. 9). The deformation on the thrust front is the most important at the axis of the main structures of the Argentera. This thrust front is located at the base of the margin near Imperia and propagated toward the top close to the western edge of the Nice arc (fig. 10). Our observations suggest that the deformations propagate offshore in relation with the advance of the Alpine front toward the south. Conclusion. – The analysis of 70 seismic reflection profiles based on stratigraphic and structural studies allows us to quantify and date the deformation of the Ligurian margin increasing eastward. This deformation dated at the Lower-Upper Pliocene limit is due to the propagation of a blind thrust front consistent with the basement tectonic deformation of this period reactivating the Oligocene rifting structures.