Birth and rapid subcellular adaptation of a hominoid-specific CDC14 protein

Gene duplication was prevalent during hominoid evolution, yet little is known about the functional fate of new ape gene copies. We characterized the CDC14B cell cycle gene and the functional evolution of its hominoid-specific daughter gene, CDC14Bretro. We found that CDC14B encodes four different splice isoforms that show different subcellular localizations (nucleus or microtubule-associated) and functional properties. A microtubular CDC14B variant spawned CDC14Bretro through retroposition in the hominoid ancestor 18-25 million years ago (Mya). CDC14Bretro evolved brain-/testis-specific expression after the duplication event and experienced a short period of intense positive selection in the African ape ancestor 7-12 Mya. Using resurrected ancestral protein variants, we demonstrate that by virtue of amino acid substitutions in distinct protein regions during this time, the subcellular localization of CDC14Bretro progressively shifted from the association with microtubules (stabilizing them) to an association with the endoplasmic reticulum. CDC14Bretro evolution represents a paradigm example of rapid, selectively driven subcellular relocalization, thus revealing a novel mode for the emergence of new gene function

Evaluation of the immune response to infection with metastatic and non-metastatic "Leishmania guyanensis" parasites

ABSTRACT : Les infections par le parasite Leishmania guyanensis se caractérisent par une dissémination depuis le site initial d'infection jusqu'aux tissus naso-pharyngés, responsable de la Leishmaniose à lésions secondaires muco-cutanées (LMC). Les lésions des patients atteints de LMC montrent une massive infiltration de cellules immunitaires, une réponse immunitaire élevée et la présence de parasites (bien qu'en très faible quantité). La LMC engendre une augmentation de l'expression de TNFa ainsi qu'un défaut dans le contrôle de la réponse immunitaire caractérisé par une absence de réponse à l'IL 10. La réponse immunitaire de l'hôte ainsi que la virulence du parasite sont deux facteurs reconnus pour le contrôle de l'infection. Le mécanisme de la pathogenèse de la LMC restent grandement incompris, surtout le mécanisme de dissémination de l'infection du site d'inoculation jusqu'aux sites secondaires d'infection (métastases) ainsi que les détails de la réponse de l'hôte contre le pathogène. Dans un modèle d'infection d' hamsters avec des parasites du Nouveau Monde, la classification des parasites Leishmania se fait en fonction de leur capacité à développer des métastases. Ce modéle d'infection a permis de caractériser différentes souches de parasites selon la classification de l'Organisation Mondiale de la Sante (OMS) tel que la souche de référence W>É-II/BR/78/M5313 qui est reconnue comme hautement métastatique alors que ces clones dérivés de M5313 montrent de grandes variations quand a leur capacité à créer des métastases. Les clones 13 et 21 sont métastatiques (M+) alors que les clones 3 et 17 sont nonmétastatiques (NI-). Les objectifs de cette thèse ont été d'étudier le rôle de la réponse immunitaire innée des macrophages après infection in vitro avec différents clones métastatiques et non-métastatiques du parasite L. guyanensis, ainsi que d'étudier la réponse immunitaire générée suite à une infection in vivo par les clones M+ et M- de L. guyanensis dans un modèle marin. L'analyse de la .réponse immunitaire des macrophages in vitro montrent qu'il y aune augmentation significative de leur statut d'activation après infection par des parasites M+ indiquée par la modulation des marqueurs d'activation de surface CD80, CD86 et CD40, ainsi que une augmentation significative de CXCL 10, CCLS, IL6 et TNFa au niveau transcription de l'ARNm et au niveau de la protéine. Cette phénomène d'activation a été observée chez les deux souches de souris C57BL/6 et BALB/c. L'utilisation d'un inhibiteur d'entrée des parasites (Cytochalsin D) ou d'un inhibiteur des fonctions endosomales (Chloroquine) diminue de manière significative la réponse des macrophages aux parasites M+. L'utilisation de macrophages déficients en TLR, MyD88, et TRIF a démontré que la réponse générée après infection par les parasites M+ était dépendante de la voie de signalisation de TRIF et TLR3. Lors d'infection in vivo par des parasites M5313, au moins 50% des souris BALB/c présentent un phénotype sensible caractérisé par des lésions non-nécrotiques qui ne guérissent pas, persistent plus de 13 semaines après infection et contiennent un nombre considérable de parasites. Ces souris développent une réponse immunitaire de type T helper 2 (Th2) avec un niveau élevé d'IL-4 et d'IL-10. Les autres souris ont un phénotype non-sensible, les souris développant peu ou pas de lésion, avec peu de parasites et une réponse immunitaire diminuée, caractérisée par un niveau faible d'IFNy, d'IL4 et d'IL10. De plus, les souris BALB/c infectées par un parasite L. guyanensis isolé à partir des lésions muco-cutanées d'un patient humain atteint de LMC ont démontrés un phénotype similaire aux souris infectées par la souche M5313 avec 50% des souris développant des lésions persistantes, alors qu'un parasite dérivé des lésions cutanées humains n'a montré qu'une faible sensibilité avec une lésion transitoire qui finit par guérir. Nous avons montré que la sensibilité de ces souris BALB/c dépend de l'IL-4 et de l'IL-10 car les souris IL-10-/sur fond génétique BALB/c ainsi que les souris BALB/c traitée avec de l'anti-IL4 étaient capables de contrôler l'infection par M5313. Les souris C57BL/6 sont résistantes à l'infection par le parasite M5313. Elles développent une lésion transitoire qui guérit 9 semaines après infection. Ces souris résistantes ont un très faible taux de parasites au site d'infection et développent une réponse immunitaire de type Thl avec un niveau élevé d'IFNr et peu d'IL4 et d'IL10. Les infections in vivo de souris déficientes en MyD88, TRIF, TLR3 ou TLR9 (sur fond génétique C57BL/6) ont indiqué que MyD88 et TLR9 étaient impliqués dans la résistance à l'infection par L. guyanensi, et que TRIF et TLR3 avaient un rôle important dans la sensibilité. Ce travail met en évidence le fait que la réponse immunitaire de l'hôte est modulée par le parasite selon leur caractérisation d'être soit M+ ou M-. Nous avons démontré également que plusieurs gènes et voies de signalisations étaient impliqués dans cette réponse favorisant le développement d'une LMC. ABSTRACT : Leishmania guyanensis parasites are able to disseminate from the initial site of cutaneous skin infection to the nasopharyngeal tissues resulting in destructive secondary lesions and the disease Mucocutaneous Leishmaniasis (MCL). The secondary lesions in patients have intense immune cell infiltration, elevated immune responses and the presence (albeit at low levels) of parasites. More specifically, MCL patients produce higher levels of TNFa and display impairment in their ability to control the immune response due to a defect in their ability to respond to IL10. Little is known about the pathogenesis of MCL, especially about the dissemination of the infection from the site of inoculation to secondary sites (metastasis) and the response of the host to the pathogen. The hamster model of L. guyanensis infection has previously characterized the WHO reference strain, L. guyanensis WHI/BR/78/M5313, as being highly metastatic. Clones of parasites derived from this reference strain show a differential ability to metastasize. This thesis studied the differential immune response generated by macrophages in vitro, or by mice in vivo, following infection with L. guyanensis parasites. A significant increase in the activation status of macrophages derived from C57BL/6 or BALB/c mice was observed after in vitro infection with L. guyanensis parasites when compared to non-metastatic parasites. This change in status was evidenced by the increased expression of surface activation markers, together with the chemokines, CXCL 10, CCLS, and cytokines, IL6 and TNFa. Furthermore, in vitro infection of macrophages isolated from mice deficient in either a specific Toll Like Receptor (TLR) or the adaptor molecules MyD88 or TRIF, indicated that the immune response generated following L. guyanensis metastatic parasite infection was reliant on the TRIF dependent TLR3 signalling pathway. In vivo footpad infection of BALB/c mice with the L. guyanensis M5313 parasites showed a reproducible susceptible phenotype, whereby at least 50% of infected mice developed non-healing, nonnecrosing lesions with high parasitemia that persisted over 13 weeks post infection. This phenotype was characterized by a Th2 type cytokine immune response with increased levels of IL4 and IL10 detected in the draining lymph nodes. IL 10 deficient mice on a BALB/c background, or BALB/c mice treated with anti-IL4 were able to control infection with L. guyanensis M5313 parasites, thereby proving that these cytokines were indeed implicated in the susceptibility to infection. Moreover, infection of BALB/c mice with patient isolated L. guyanensis parasites confirmed that MCL derived parasites were able to induce a susceptibility phenotype similar to that of L. guyanensis M5313. C57BL/6 mice, on the other hand, were highly resistant to infection with L. guyanensis M5313 parasites and produced transient footpad swelling that healed by week 9 post infection, together with low degrees of footpad parasitemia and a Thl polarized immune response. Infection of mice deficient in MyD88, TRIF, TLR3, and TLR9 (on a C57BL/6 background), indicated that MyD88 and TLR9 were involved in the resistance of these mice to infection, and that TRIF and TLR3 were involved in the susceptibility. This study has shown that the host response can be differentially modulated depending on the infecting parasite with several genes and pathways being identified that could be involved in promoting the development of MCL.

Iowa 2008 Summer Storms After-Action Report, April 27, 2009

In the summer of 2008, the state of Iowa suffered from a series of severe storms that produced tornadoes and heavy rainfall, which resulted in widespread flooding. The Summer Storms1 lasted from late May through mid-August, with the most intense storms occurring over a month-long period from May 25 to June 25. The Summer Storms exacted a major human and economic toll on Iowa, resulting in 18 fatalities and 106 injuries, forcing the evacuation of approximately 38,000 Iowans, and impacting 21,000 housing units. Iowa’s public and private sectors suffered significant monetary damages. Eighty-six of the ninety-nine counties in the state were included in the Governor’s disaster declarations.

Palliative and supportive care: at the frontier of medical omnipotence.

Cancer patients have physical, social, spiritual an emotional needs. They may suffer from severe physical symptoms, from social isolation and a sense of spiritual abandonment, and emotions such as sadness and anxiety, or feeling of deception, helplessness, anger and guilt. In some of them, the disease is rapidly progressive and they ultimately die. Their demanding care evokes intense feelings in health care providers, the more so since these incurable patients represent a challenge, which can be characterized as one of 'medical omnipotence'. It may be assumed that the way health care providers cope with these circumstances profoundly influences the way these patients are cared for. Attitudes regarding the emerging heterogeneous movement of palliative and supportive care and its different models of implementation can be viewed form this vantage point. Here we look at these interrelations and discuss the potential pitfalls if they are ignored and remain unexamined.

Candida colonization index and subsequent infection in critically ill surgical patients: 20 years later.

INTRODUCTION: For decades, clinicians dealing with immunocompromised and critically ill patients have perceived a link between Candida colonization and subsequent infection. However, the pathophysiological progression from colonization to infection was clearly established only through the formal description of the colonization index (CI) in critically ill patients. Unfortunately, the literature reflects intense confusion about the pathophysiology of invasive candidiasis and specific associated risk factors. METHODS: We review the contribution of the CI in the field of Candida infection and its development in the 20 years following its original description in 1994. The development of the CI enabled an improved understanding of the pathogenesis of invasive candidiasis and the use of targeted empirical antifungal therapy in subgroups of patients at increased risk for infection. RESULTS: The recognition of specific characteristics among underlying conditions, such as neutropenia, solid organ transplantation, and surgical and nonsurgical critical illness, has enabled the description of distinct epidemiological patterns in the development of invasive candidiasis. CONCLUSIONS: Despite its limited bedside practicality and before confirmation of potentially more accurate predictors, such as specific biomarkers, the CI remains an important way to characterize the dynamics of colonization, which increases early in patients who develop invasive candidiasis.

Effects of recreational fishing on three fish species from the Posidonia oceanica meadows off Minorca (Balearic archipelago, western Mediterranean)

Experimental fishing and visual censuses were conducted at nine Posidonia oceanica sites off Minorca exposed to different levels of fishing intensity to assess the effects of recreational fishing on the species that dominate the catch. Total catch per unit effort (CPUE) was highly seasonal and a statistically significant interaction term existed between the season and the level of fishing intensity. CPUE decreased everywhere at the end of the fishing season (autumn), but such a reduction was more intense at those sites exposed to the highest level of fishing. Visual censuses confirmed that there was a lower abundance of vulnerable fish in autumn. Differences vanished in spring probably because fish reshuffled between the considered sites throughout the winter, when the level of fishing intensity was extremely low. Although the average total lengths of Serranus scriba and Diplodus annularis were unaffected by the level of fishing intensity, the average total length of Coris julis was smaller at the most heavily fished sites. In conclusion, recreational fishing has a relevant impact on most of the exploited species and some of the seasonality reported for the Posidonia oceanica fish assemblages might be caused by the seasonality of the fishery.

Perforation cardiaque d'un ulcère gastrique: une cause inhabituelle de décès, après résection oesogastrique pour carcinome épidermoïde de l'oesophage [Cardiac perforation by a gastric ulcer: an unusual cause of death, after an esophageal and gastric resection of an epidermoid esophageal carcinoma]

We report here the case of a 55 year old female that underwent surgery for a well differentiated squamous cell carcinoma of the esophagus (middle third). Four months after surgery, she complains of neck pain, for which she is prescribed non steroidal antiinflammatory drugs (NSAID). A CT-scan and a Barium swallow are then normal. After three weeks of treatment, the patient is admitted on emergency to the Intensive Care Unit for a resuscitation hematemesis and atrial fibrillation with a fast ventricular response. The symptoms are stabilized after the transfusion of a few packed red blood cells. A few hours later, however, a massive hematemesis recurs and the patient dies despite intense resuscitation measures. Autopsy reveals three gastric ulcers, one of which had perforated through the cardiac left ventricular wall

Mineralogical, K-Ar, stable and Sr isotope systematics of K-white micas during very low-grade metamorphism of limestones (Helvetic nappes, Western Switzerland)

Mineralogical, K-Ar, Rb-Sr and stable isotope analyses have been carried out on K-white micas from Helvetic Malm limestones in order to examine their evolution during very low- to low-grade Alpine metamorphism, associated with intense ductile deformation. Metamorphic temperatures were estimated al approximately 300-degrees-C from stable isotopes (quartz-calcite thermometry), occurrence of chloritoid, and `'epizonal'' illite crystallinity index. K-white micas consist of variable mixtures of 2M, phengite and muscovite, as revealed by detailed X-ray diffraction analyses using peak decomposition of the (060, 331) spectra. K-Ar apparent ages display a strong grain-size dependence in which mainly fine-grained size fractions (< 2 mum) record Alpine ages (37-15 Ma). However, these ages provide a relative rather than an absolute chronology of the diachronous Alpine metamorphic evolution of the Helvetic nappes. The resetting of the K-Ar isotopic system of K-white micas to Alpine metamorphic conditions reflects an apparent combination of crystallization/recrystallization and radiogenic Ar-40 diffusion loss. The oxygen isotope compositions of micas (+ 15 to + 22 parts per thousand) are intermediate between detrital and O-18-enriched values expected for micas neoformed within an abundant marine carbonate matrix. No isotopic equilibrium has been reached between calcite and micas. The variable depletion of hydrogen isotope compositions (- 126 to - 82 parts per thousand) is influenced by the interaction with organic matter under closed-system conditions. Organic matter, if not removed, may also represent a serious source of error in K-Ar age determination, by introducing radiogenic Ar-40 contamination. Sr-87/Sr-86 isotope ratios of micas range from 0.70879 to 0.70902 with one outlier at 0.71794. The low values reflect Sr exchange with calcite occurring during crystallization/recrystallization of micas under closed-system conditions.

Protein kinase C-zeta mediates retinal degeneration in response to TNF.

Tumor necrosis factor-alpha (TNF) has been implicated in retinal ganglion cells (RGC) degeneration in glaucoma. Atypical protein kinase C (PKC) zeta is involved in cell protection against various stresses. The aim of this study was to investigate the potential proapoptotic effects of intravitreal injections of TNF with or without PKCzeta specific inhibitor on the rat retina. TNF was injected in the vitreous of rat eyes alone or in combination with specific PKCzeta inhibitor. PKCzeta and NF-kappaB were studied by immunohistochemistry and western-blotting analysis on retina, and apoptosis quantified by the TUNEL assay. While low basal PKCzeta was observed in the control eyes, TNF induced intense expression of PKCzeta mostly in bipolar cells processes. PKCzeta staining became nuclear when TNF was coinjected with PKCzeta inhibitor. TNF alone did not induce apoptosis in the retina. Coinjection of the PKCzeta-specific inhibitor and TNF, however, induced apoptosis in the inner nuclear and ganglion cell layers. The PKCzeta-specific inhibitor unmasks retinal cells to TNF cytotoxicity showing a link between the proapoptotic effects of TNF and the antiapoptotic PKCzeta signaling pathway.

Risk perception and emotional coping: a pathway for behavioural addiction?

This article summarizes current concepts of the working memory with regard to its role within emotional coping strategies. In particular, it focuses on the fact that the limited capacity of the working memory to process now-relevant information can be turned into an advantage, when the individual is occupied by dealing with unpleasant emotion. Based on a phenomenon known as dual-task interference (DTI), this emotion can be chased by intense arousal due to clearly identifiable external stressors. Thus, risk perception might be used as a 'DTI inductor' that allows avoidance of unpleasant emotion. Successful mastery of risk adds a highly relevant dopaminergic component to the overall experience. The resulting mechanism of implicit learning may contribute to the development of a behavioural addiction. Besides its putative effects in the development of a behavioural addiction, the use of DTI might be of a more general interest for the clinical practice, especially in the field of psychotherapy. © 2013 S. Karger AG, Basel.

La investigación regional en España: un análisis bibliométrico

Trabajos recientes han puesto de manifiesto que la búsqueda española en economía realizada durante la década de los noventa ha incrementado su presencia internacional al mismo tiempo que se observa una dualidad a la difusión de la búsqueda a través de revistas nacionales e internacionales en función del ámbito de búsqueda considerado. Este trabajo analiza, a partir de la aplicación de técnicas bibliométricas que ha sido la evolución de la búsqueda regional y urbana realizada en España dentro del contexto internacional y si hay diferencias muy marcadas entre la búsqueda publicada a revistas nacionales y la publicada a revistas internacionales durante el periodo 1991-2000. Los resultados obtenidos muestran que la tendencia observada por el conjunto de la economía también se han producido (incluso con más intensidad) dentro del ámbito de la búsqueda centrada en aspectos regionales y urbanos

A coherent neurobiological framework for functional neuroimaging provided by a model integrating compartmentalized energy metabolism.

Functional neuroimaging has undergone spectacular developments in recent years. Paradoxically, its neurobiological bases have remained elusive, resulting in an intense debate around the cellular mechanisms taking place upon activation that could contribute to the signals measured. Taking advantage of a modeling approach, we propose here a coherent neurobiological framework that not only explains several in vitro and in vivo observations but also provides a physiological basis to interpret imaging signals. First, based on a model of compartmentalized energy metabolism, we show that complex kinetics of NADH changes observed in vitro can be accounted for by distinct metabolic responses in two cell populations reminiscent of neurons and astrocytes. Second, extended application of the model to an in vivo situation allowed us to reproduce the evolution of intraparenchymal oxygen levels upon activation as measured experimentally without substantially altering the initial parameter values. Finally, applying the same model to functional neuroimaging in humans, we were able to determine that the early negative component of the blood oxygenation level-dependent response recorded with functional MRI, known as the initial dip, critically depends on the oxidative response of neurons, whereas the late aspects of the signal correspond to a combination of responses from cell types with two distinct metabolic profiles that could be neurons and astrocytes. In summary, our results, obtained with such a modeling approach, support the concept that both neuronal and glial metabolic responses form essential components of neuroimaging signals.

Influence of early antioxidant supplements on clinical evolution and organ function in critically ill cardiac surgery, major trauma, and subarachnoid hemorrhage patients.

INTRODUCTION: Oxidative stress is involved in the development of secondary tissue damage and organ failure. Micronutrients contributing to the antioxidant (AOX) defense exhibit low plasma levels during critical illness. The aim of this study was to investigate the impact of early AOX micronutrients on clinical outcome in intensive care unit (ICU) patients with conditions characterized by oxidative stress. METHODS: We conducted a prospective, randomized, double-blind, placebo-controlled, single-center trial in patients admitted to a university hospital ICU with organ failure after complicated cardiac surgery, major trauma, or subarachnoid hemorrhage. Stratification by diagnosis was performed before randomization. The intervention was intravenous supplements for 5 days (selenium 270 microg, zinc 30 mg, vitamin C 1.1 g, and vitamin B1 100 mg) with a double-loading dose on days 1 and 2 or placebo. RESULTS: Two hundred patients were included (102 AOX and 98 placebo). While age and gender did not differ, brain injury was more severe in the AOX trauma group (P = 0.019). Organ function endpoints did not differ: incidence of acute kidney failure and sequential organ failure assessment score decrease were similar (-3.2 +/- 3.2 versus -4.2 +/- 2.3 over the course of 5 days). Plasma concentrations of selenium, zinc, and glutathione peroxidase, low on admission, increased significantly to within normal values in the AOX group. C-reactive protein decreased faster in the AOX group (P = 0.039). Infectious complications did not differ. Length of hospital stay did not differ (16.5 versus 20 days), being shorter only in surviving AOX trauma patients (-10 days; P = 0.045). CONCLUSION: The AOX intervention did not reduce early organ dysfunction but significantly reduced the inflammatory response in cardiac surgery and trauma patients, which may prove beneficial in conditions with an intense inflammation. TRIALS REGISTRATION: Clinical Trials.gov RCT Register: NCT00515736.

Magnetization reversal and magnetic anisotropies in epitaxial Fe/MgO and Fe/MgO/Fe heterostructures grown on Si(001)

Epitaxial Fe/MgO heterostructures have been grown on Si(001) by a combination of sputtering and laser ablation deposition techniques. The growth of MgO on Si(001) is mainly determined by the nature of the interface, with large lattice mismatch and the presence of an amorphous layer of unclear origin. Reflection high energy electron diffraction patterns of this MgO buffer layer are characteristic of an epitaxial, but disordered, structure. The structural quality of subsequent Fe and MgO layers continuously improves due to the better lattice match and the burial of defects. A weak uniaxial in-plane magnetic anisotropy is found superimposed on the expected cubic biaxial anisotropy. This additional anisotropy, of interfacial nature and often found in Fe/MgO and Fe/MgO/GaAs(001) systems, is less intense here due to the poorer MgO/Si interface quality compared with that of other systems. From the evolution of the anisotropy field with film thickness, magnetic anisotropy is also found to depend on the crystal quality. Kerr measurements of a Fe/MgO multilayered structure grown on Si show two different switching fields, suggesting magnetic coupling of two of the three Fe layers. Nevertheless, due to the little sensitivity to the bottom Fe film, independent switching of the three layers cannot be ruled out.

La investigación regional en España: un análisis bibliométrico

Trabajos recientes han puesto de manifiesto que la búsqueda española en economía realizada durante la década de los noventa ha incrementado su presencia internacional al mismo tiempo que se observa una dualidad a la difusión de la búsqueda a través de revistas nacionales e internacionales en función del ámbito de búsqueda considerado. Este trabajo analiza, a partir de la aplicación de técnicas bibliométricas que ha sido la evolución de la búsqueda regional y urbana realizada en España dentro del contexto internacional y si hay diferencias muy marcadas entre la búsqueda publicada a revistas nacionales y la publicada a revistas internacionales durante el periodo 1991-2000. Los resultados obtenidos muestran que la tendencia observada por el conjunto de la economía también se han producido (incluso con más intensidad) dentro del ámbito de la búsqueda centrada en aspectos regionales y urbanos