Murine lymphoid procoagulant activity induced by bacterial lipopolysaccharide and immune complexes is a monocyte prothrombinase

Murine lymphoid cells respond rapidly to bacterial lipopolysaccharide or antigen-antibody complexes to initiate or accelerate the blood coagulation pathways. The monocyte or macrophage has been identified as the cellular source, although lymphocyte collaboration is required for the rapid induction of the procoagulant response. This procoagulant activity is identified in the present study as a direct prothrombin activator, i.e., a prothrombinase. Studies with plasmas deficient in single coagulation factors demonstrate that the induced murine procoagulant activity effector molecule does not require factors XII, VIII, VII, X, or V, but does require prothrombin to transform fibrinogen to fibrin. This enzyme(s) produces limited proteolysis of prothrombin to yield thrombin or thrombinlike products that are functionally capable of converting fibrinogen to fibrin. The prothrombinase is undetectable in freshly isolated Murine lymphoid cells respond rapidly to bacterial lipopolysaccharide or antigen-antibody complexes to initiate or accelerate the blood coagulation pathways. The monocyte or macrophage has been identified as the cellular source, although lymphocyte collaboration is required for the rapid induction of the procoagulant response. This procoagulant activity is identified in the present study as a direct prothrombin activator, i.e., a prothrombinase. Studies with plasmas deficient in single coagulation factors demonstrate that the induced murine procoagulant activity effector molecule does not require factors XII, VIII, VII, X, or V, but does require prothrombin to transform fibrinogen to fibrin. This enzyme(s) produces limited proteolysis of prothrombin to yield thrombin or thrombinlike products that are functionally capable of converting fibrinogen to fibrin. The prothrombinase is undetectable in freshly isolate

Survivin as a therapeutic target in Sonic hedgehog-driven medulloblastoma.

Medulloblastoma (MB) is a highly malignant brain tumor that occurs primarily in children. Although surgery, radiation and high-dose chemotherapy have led to increased survival, many MB patients still die from their disease, and patients who survive suffer severe long-term side effects as a consequence of treatment. Thus, more effective and less toxic therapies for MB are critically important. Development of such therapies depends in part on identification of genes that are necessary for growth and survival of tumor cells. Survivin is an inhibitor of apoptosis protein that regulates cell cycle progression and resistance to apoptosis, is frequently expressed in human MB and when expressed at high levels predicts poor clinical outcome. Therefore, we hypothesized that Survivin may have a critical role in growth and survival of MB cells and that targeting it may enhance MB therapy. Here we show that Survivin is overexpressed in tumors from patched (Ptch) mutant mice, a model of Sonic hedgehog (SHH)-driven MB. Genetic deletion of survivin in Ptch mutant tumor cells significantly inhibits proliferation and causes cell cycle arrest. Treatment with small-molecule antagonists of Survivin impairs proliferation and survival of both murine and human MB cells. Finally, Survivin antagonists impede growth of MB cells in vivo. These studies highlight the importance of Survivin in SHH-driven MB, and suggest that it may represent a novel therapeutic target in patients with this disease

Pharmacokinetics of Tacrolimus in Kidney Transplant Recipients: Twice Daily Versus Once Daily Dosing

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72008/1/j.1600-6143.2004.00383.x.pd

YBCO-based non-volatile ReRAM tested in Low Earth Orbit

An YBCO-based test structure corresponding to the family of ReRAM devices associated with the valence change mechanism is presented. We have characterized its electrical response previous to its lift-off to a Low Earth Orbit (LEO) using standard electronics and also with the dedicated LabOSat-01 controller. Similar results were obtained in both cases. After about 200 days at LEO on board a small satellite, electrical test started on the memory device using the LabOSat-01 controller. We discuss the results of the first 150 tests, performed along a 433-day time interval in space. The memory device remained operational despite the hostile conditions that involved launching, lift-off vibrations, permanent thermal cycling, and exposure to ionizing radiation, with doses 3 orders of magnitude greater than the usual ones on Earth. The device showed resistive switching and IV characteristics similar to those measured on Earth, although with changes that follow a smooth drift in time. A detailed study of the electrical transport mechanisms, based on previous models that indicate the existence of various conducting mechanisms through the metal-YBCO interface showed that the observed drift can be associated with a local temperature drift at the LabOSat controller, with no clear evidence that allows determining changes in the underlying microscopic factors. These results show the reliability of complex-oxide non-volatile ReRAM-based devices in order to operate under all the hostile conditions encountered in space-borne applications

Recombination rate and selection strength in HIV intra-patient evolution

The evolutionary dynamics of HIV during the chronic phase of infection is driven by the host immune response and by selective pressures exerted through drug treatment. To understand and model the evolution of HIV quantitatively, the parameters governing genetic diversification and the strength of selection need to be known. While mutation rates can be measured in single replication cycles, the relevant effective recombination rate depends on the probability of coinfection of a cell with more than one virus and can only be inferred from population data. However, most population genetic estimators for recombination rates assume absence of selection and are hence of limited applicability to HIV, since positive and purifying selection are important in HIV evolution. Here, we estimate the rate of recombination and the distribution of selection coefficients from time-resolved sequence data tracking the evolution of HIV within single patients. By examining temporal changes in the genetic composition of the population, we estimate the effective recombination to be r=1.4e-5 recombinations per site and generation. Furthermore, we provide evidence that selection coefficients of at least 15% of the observed non-synonymous polymorphisms exceed 0.8% per generation. These results provide a basis for a more detailed understanding of the evolution of HIV. A particularly interesting case is evolution in response to drug treatment, where recombination can facilitate the rapid acquisition of multiple resistance mutations. With the methods developed here, more precise and more detailed studies will be possible, as soon as data with higher time resolution and greater sample sizes is available.Comment: to appear in PLoS Computational Biolog

Global Development and Climate Change: A Game Theory Approach

The increasing concern with climate change is one of the main issues of our time, and thus we aim to theoretically and mathematically analyse its causes. However our approach follows a different stream of thought, presenting the reasoning and decision-making processes between technical and moral solutions. We have resorted to game theory models in order to demonstrate cooperative and non-cooperative scenarios, ranging from the traditional to the evolutionary within game theory. In doing so we are able to glimpse the development of modern society and a paradigm shift regarding human control over nature and to what extent it is harmful to the sustainability of our environment and the survival of future generations. Merging different fields of knowledge, we present a theoretical-philosophical approach, combined with empirical-mathematical solutions taking into account the agent-based behaviour guided blindly by instrumental rationality

Comparison of m-mode echocardiographic left ventricular mass measured using digital and strip chart readings: The Atherosclerosis Risk in Communities (ARIC) study

BACKGROUND: Epidemiological and clinical studies frequently use echocardiography to measure LV wall thicknesses and chamber dimension for estimating quantitative measures of LV mass. While echocardiographic M-mode LV images have traditionally been measured using hand-held calipers and strip-chart paper tracings, digitized M-mode LV image measurements made directly on the computer screen using electronic calipers have become standard practice. We sought to determine if systematic differences in LV mass occur between the two methods by comparing LV mass measured from simultaneous M-mode strip chart recordings and digitized recordings. METHODS: The Atherosclerosis Risk in Communities study applied the latter method. To determine if systematic differences in LV mass occur between the two methods, LV mass was measured from simultaneous M-mode strip chart recordings and digitized recordings. RESULTS: We found no difference in LV mass (p > .25) and a strong correlation in LV mass between the two methods (r = 0.97). Neither age, sex, nor hypertension status affected the correlation of LV mass between the two methods. CONCLUSIONS: We conclude that digital estimates of LV mass provide unbiased estimates comparable to the strip-chart method

Reduced expression of the glucocorticoid receptor in the hippocampus of patients with drug-resistant temporal lobe epilepsy and comorbid depression

Objective: Depressive disorders are common among about 50% of the patients with drug-resistant temporal lobe epilepsy (TLE). The underlying etiology remains elusive, but hypothalamus-pituitary-adrenal (HPA) axis activation due to changes in glucocorticoid receptor (GR) protein expression could play an important role. Therefore, we set out to investigate expression of the GR in the hippocampus, an important brain region for HPA axis feedback, of patients with drug-resistant TLE, with and without comorbid depression. Methods: GR expression was studied using immunohistochemistry on hippocampal sections from well-characterized TLE patients with depression (TLE + D, n = 14) and without depression (TLE − D, n = 12) who underwent surgery for drug-resistant epilepsy, as well as on hippocampal sections from autopsy control cases (n = 9). Video–electroencephalography (EEG), magnetic resonance imaging (MRI), and psychiatric and memory assessments were performed prior to surgery. Results: Abundant GR immunoreactivity was present in dentate gyrus granule cells and CA1 pyramidal cells of controls. In contrast, neuronal GR expression was lower in patients with TLE, particularly in the TLE + D group. Quantitative analysis showed a smaller GR+ area in TLE + D as compared to TLE − D patients and controls. Furthermore, the ratio between the number of GR+/NeuN+ cells was lower in patients with TLE + D as compared to TLE − D and correlated negatively with the depression severity based on psychiatric history. The expression of the GR was also lower in glial cells of TLE + D compared to TLE − D patients and correlated negatively to the severity of depression. Significance: Reduced hippocampal GR expression may be involved in the etiology of depression in patients with TLE and could constitute a biological marker of depression in these patients.Fil: D`alessio, Luciana. Universidad Nacional Arturo Jauretche. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos. Provincia de Buenos Aires. Ministerio de Salud. Hospital Alta Complejidad en Red El Cruce Dr. Néstor Carlos Kirchner Samic. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Centro Universitario de Neurología "Dr. José María Ramos Mejía".; ArgentinaFil: Mesarosova, Lucia. University of Amsterdam; Países BajosFil: Anink, Jasper J.. University of Amsterdam; Países BajosFil: Kochen, Sara Silvia. Universidad Nacional Arturo Jauretche. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos. Provincia de Buenos Aires. Ministerio de Salud. Hospital Alta Complejidad en Red El Cruce Dr. Néstor Carlos Kirchner Samic. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Centro Universitario de Neurología "Dr. José María Ramos Mejía".; ArgentinaFil: Solis, Patricia Cristina Lourdes. Universidad Nacional Arturo Jauretche. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos. Provincia de Buenos Aires. Ministerio de Salud. Hospital Alta Complejidad en Red El Cruce Dr. Néstor Carlos Kirchner Samic. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Centro Universitario de Neurología "Dr. José María Ramos Mejía".; ArgentinaFil: Oddo, Silvia Andrea. Universidad Nacional Arturo Jauretche. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos. Provincia de Buenos Aires. Ministerio de Salud. Hospital Alta Complejidad en Red El Cruce Dr. Néstor Carlos Kirchner Samic. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Centro Universitario de Neurología "Dr. José María Ramos Mejía".; ArgentinaFil: Konopka, Hector Felix. Universidad Nacional Arturo Jauretche. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos. Provincia de Buenos Aires. Ministerio de Salud. Hospital Alta Complejidad en Red El Cruce Dr. Néstor Carlos Kirchner Samic. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Centro Universitario de Neurología "Dr. José María Ramos Mejía".; ArgentinaFil: Iyer, Anand M.. University of Amsterdam; Países BajosFil: Mühlebner, Angelika. University of Amsterdam; Países BajosFil: Lucassen, Paul J.. University of Amsterdam; Países BajosFil: Aronica, Eleonora. University of Amsterdam; Países Bajos. Stichting Epilepsie Instellingen Nederland; Países BajosFil: van Vliet, Erwin A.. University of Amsterdam; Países Bajo