A novel human aquaporin-4 splice variant exhibits a dominant-negative activity: a new mechanism to regulate water permeability.

Two major isoforms of aquaporin-4 (AQP4) have been described in human tissue. Here we report the identification and functional analysis of an alternatively spliced transcript of human AQP4, AQP4-Δ4, that lacks exon 4. In transfected cells AQP4-Δ4 is mainly retained in the endoplasmic reticulum and shows no water transport properties. When AQP4-Δ4 is transfected into cells stably expressing functional AQP4, the surface expression of the full-length protein is reduced. Furthermore, the water transport activity of the cotransfectants is diminished in comparison to transfectants expressing only AQP4. The observed down-regulation of both the expression and water channel activity of AQP4 is likely to originate from a dominant-negative effect caused by heterodimerization between AQP4 and AQP4-Δ4, which was detected in coimmunoprecipitation studies. In skeletal muscles, AQP4-Δ4 mRNA expression inversely correlates with the level of AQP4 protein and is physiologically associated with different types of skeletal muscles. The expression of AQP4-Δ4 may represent a new regulatory mechanism through which the cell-surface expression and therefore the activity of AQP4 can be physiologically modulated.

Strong time dependence of the 76-gene prognostic signature for node-negative breast cancer patients in the TRANSBIG multicenter independent validation series.

PURPOSE: Recently, a 76-gene prognostic signature able to predict distant metastases in lymph node-negative (N(-)) breast cancer patients was reported. The aims of this study conducted by TRANSBIG were to independently validate these results and to compare the outcome with clinical risk assessment. EXPERIMENTAL DESIGN: Gene expression profiling of frozen samples from 198 N(-) systemically untreated patients was done at the Bordet Institute, blinded to clinical data and independent of Veridex. Genomic risk was defined by Veridex, blinded to clinical data. Survival analyses, done by an independent statistician, were done with the genomic risk and adjusted for the clinical risk, defined by Adjuvant! Online. RESULTS: The actual 5- and 10-year time to distant metastasis were 98% (88-100%) and 94% (83-98%), respectively, for the good profile group and 76% (68-82%) and 73% (65-79%), respectively, for the poor profile group. The actual 5- and 10-year overall survival were 98% (88-100%) and 87% (73-94%), respectively, for the good profile group and 84% (77-89%) and 72% (63-78%), respectively, for the poor profile group. We observed a strong time dependence of this signature, leading to an adjusted hazard ratio of 13.58 (1.85-99.63) and 8.20 (1.10-60.90) at 5 years and 5.11 (1.57-16.67) and 2.55 (1.07-6.10) at 10 years for time to distant metastasis and overall survival, respectively. CONCLUSION: This independent validation confirmed the performance of the 76-gene signature and adds to the growing evidence that gene expression signatures are of clinical relevance, especially for identifying patients at high risk of early distant metastases.

The stable hydrogen and oxygen isotope variation of water stored in polyethylene terephthalate (PET) bottles

A set of bottled waters from a single natural spring distributed worldwide in polyethylene terephthalate (PET) bottles has been used to examine the effects of storage in plastic polymer material on the isotopic composition (delta(18)O and delta(2)H values) of the water. All samples analyzed were subjected to the same packaging procedure but experienced different conditions of temperature and humidity during storage. Water sorption and the diffusive transfer of water and water vapor through the wall of the PET bottle may cause isotopic exchange between water within the bottle and water vapor in air near the PET-water interface. Changes of about +4 parts per thousand for delta(2)H and +0.7 parts per thousand for delta(18)O have been measured for water after 253 days of storage within the PET bottle. The results of this study clearly indicate the need to use glass bottles for storing water samples for isotopic studies. It is imperative to transfer PET-bottled natural waters to glass bottles for their use as calibration material or potential international working standards. Copyright (C) 2008 John Wiley & Sons, Ltd.

Expression of E-Selectin and Vascular Cell Adhesion Molecule-1 in So-Called 'Negative' Appendices: First Results to Support the Pathological Diagnosis in Borderline Cases.

Background: Since the rate of histologically 'negative' appendices still ranges between 15 and 20%, appendicitis in 'borderline' cases remains a challenging disease. As previously described, cell adhesion molecule expression correlates with different stages of appendicitis. Therefore, it was of interest to determine whether the 'negative' appendix correlated with the absence of E-selectin or vascular cell adhesion molecule-1 (VCAM-1). Methods: Nineteen grossly normal appendices from a series of 120 appendectomy specimens from patients with suspected appendicitis were analysed in frozen sections for the expression of E-selectin and VCAM-1. As control, 5 normal appendices were stained. Results: This study showed a coexpression of E-selectin and VCAM-1 in endothelial cells in early and recurrent appendicitis. In patients with symptoms for less than 6 h, only E-selectin was detected. Cases with fibrosis and luminal obliteration were only positive for VCAM-1. In cases of early appendicitis with symptoms of less than 6 h duration, a discordance between histological and immunohistochemical results was found. Conclusions: This report indicates that E-selectin and VCAM-1 expression could be useful parameters in the diagnosis of appendicitis in borderline cases.

Selective expression of a dominant-negative form of peroxisome proliferator-activated receptor in keratinocytes leads to impaired epidermal healing.

Many nuclear hormone receptors are involved in the regulation of skin homeostasis. However, their role in the epithelial compartment of the skin in stress situations, such as skin healing, has not been addressed yet. The healing of a skin wound after an injury involves three major cell types: immune cells, which are recruited to the wound bed; dermal fibroblasts; and epidermal and hair follicle keratinocytes. Our previous studies have revealed important but nonredundant roles of PPARalpha and beta/delta in the reparation of the skin after a mechanical injury in the adult mouse. However, the mesenchymal or epithelial cellular compartment in which PPARalpha and beta/delta play a role could not be determined in the null mice used, which have a germ line PPAR gene invalidation. In the present work, the role of PPARalpha was studied in keratinocytes, using transgenic mice that express a PPARalpha mutant with dominant-negative (dn) activity specifically in keratinocytes. This dn PPARalpha lacks the last 13 C terminus amino acids, binds to a PPARalpha agonist, but is unable to release the nuclear receptor corepressor and to recruit the coactivator p300. When selectively expressed in keratinocytes of transgenic mice, dn PPARalphaDelta13 causes a delay in the healing of skin wounds, accompanied by an exacerbated inflammation. This phenotype, which is similar to that observed in PPARalpha null mice, strongly suggests that during skin healing, PPARalpha is required in keratinocytes rather than in other cell types.

Impact of Matrix-Assisted Laser Desorption Ionization Time-of-Flight Mass Spectrometry on the Clinical Management of Patients With Gram-negative Bacteremia: A Prospective Observational Study.

Background. Early identification of pathogens from blood cultures using matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry may optimize the choice of empirical antibiotic therapy in the setting of bloodstream infections. We aimed to assess the impact of this new technology on the use of antibiotic treatment in patients with gram-negative bacteremia. Methods. We conducted a prospective observational study from January to December 2010 to evaluate the sequential and separate impacts of Gram stain reporting and MALDI-TOF bacterial identification performed on blood culture pellets in patients with gram-negative bacteremia. The primary outcome was the impact of MALDI-TOF on empirical antibiotic choice. Results. Among 202 episodes of gram-negative bacteremia, Gram stain reporting had an impact in 42 cases (20.8%). MALDI-TOF identification led to a modification of empirical therapy in 71 of all 202 cases (35.1%), and in 16 of 27 cases (59.3%) of monomicrobial bacteremia caused by AmpC-producing Enterobacteriaceae. The most frequently observed impact was an early appropriate broadening of the antibiotic spectrum in 31 of 71 cases (43.7%). In total, 143 of 165 episodes (86.7%) of monomicrobial bacteremia were correctly identified at genus level by MALDI-TOF. Conclusions. In a low prevalence area for extended spectrum betalactamases (ESBL) and multiresistant gram-negative bacteria, MALDI-TOF performed on blood culture pellets had an impact on the clinical management of 35.1% of all gram-negative bacteremia cases, demonstrating a greater impact than Gram stain reporting. Thus, MALDI-TOF could become a vital second step beside Gram stain in guiding the empirical treatment of patients with bloodstream infection.

Paleoenvironmental evolution of the Helvetic shallow-water carbonate platform near the Barremian-Aptian boundary, and its relationship with paleoceanographic and paleoclimatic change in the Tethys

Abstract:During my doctoral research, I focused on deciphering the interactions between sea-level and climate change during the Late Barremian-Early Aptian, their expression in the Tethys basin and in the Helvetic carbonate platform. The research highlights are summarized here in three points: In the Helvetic Alps, the transition between the Lower Schrattenkalk (Upper Barremian) and the Rawil Member (Lowermost Aptian) is characterized by a change from a predominantly photozoan to a heterozoan carbonate-producing system, which coincides in time with a general increase in detrital and nutrient input. The clay mineral record shows the appearance of kaolinite within the Rawil Member, whereas this mineral is absent from the uppermost Lower and lowermost Upper Schrattenkalk Members. This indicates the installation of a warmer and more humid climate during this time period. A negative peak in 513C is recorded at the top of the Lower Schrattenkalk Member, and correlates with the well-known negative excursion of -l%o occurring in other basins and dated as latest Barremian, thus confirming a latest Barremian and earliest Aptian age for the Lower Schrattenkalk and Rawil Members, respectively. Furthermore, a sequence stratigraphie framework has been defined for the Rawil Member, based on both the ecology of faunal and floral assemblages, and their palaeoenvironmental interpretation, as well as on the stacking pattern of limestone beds observed during field prospection. The presence of a sequence boundary is postulated near the top of the Lower Schrattenkalk Member, which is correlated with the earliest Aptian SbAl defined in Vercors (France). The SbAl is characterized by a maximum of proximal assemblages and by the disappearance of several benthic foraminiferal species. Within the Rawil Member itself, the stacking pattern and microfacies trends are interpreted to represent the TST of the first Aptian sequence. With regards to the pelagic setting in the Tethyan realm, I investigated the Gorgo a Cerbara section (central Italy). There, thin organic-rich layers occur episodically in pelagic carbonates of the upper Barremian portion of the Maiolica Formation. They are associated with high Corg:Ptot ratios, which indicate the presence of intermittent dysoxic to anoxic conditions. Coarse correlations are also observed between TOC, Ρ and biogenic silica contents, indicating links between Ρ availability, productivity, and organic matter preservation. The corresponding 813Ccarb and δ180 records remain, however, quite stable, indicating that these brief periods of enhanced TOC preservation did not have sufficient impact on the marine carbon household to deviate 6,3C records, and are probably not the consequence of major climate change. On the other hand, organic-rich layers become more frequent around the Barremian-Aptian boundary in both pelagic and hemi-pelagic environments (Gorgo a Cerbara and La Bédoule, France), which are correlated with negative excursions in 6l3Ccarb and 613Corg records. During the earliest Aptian, at Gorgo a Cerbara, the frequency of organic-rich intervals progressively increases and redox-sensitive trace-element enrichments become more frequent, until the highest TOC-enriched level just below the "Livello Selli", indicator of Oceanic Anoxic Event la (OAEla). The latter is associated with the well-known negative spike in 613Ccarb and S,3Corg records, a diminution in the δ,80 record interpreted as the consequence of a wanning interval, an important peak in Ρ accumulation and high Cor::Ptot ratios indicating the prevalence of anoxic conditions. The Selli Level (OAEla) documents a general cooling phase and coincides with maximum RSTE enrichments as well as high Corg:Ptot ratios, which confirm the importance of anoxic conditions during OAE1 a at this site.During the Early Aptian, environmental change on the platform is expressed by orbitolinids proliferation that may be induced by both climate change and sea-level rise. In the basin, the successive black shales horizons from the Late Barremian until the OAE la are interpreted as the progressive impact of palaeoenvironmental change probably linked to the formation of the Ontong- Java plate-basalt plateau.RésuméCe travail de thèse a permis d'investiguer les interactions entre les variations du niveau marin et les changements climatiques sur la plate-forme helvétique ainsi qu'en domaine pélagique à la limite Barrémien-Aptien (Crétacé).Dans les Alpes helvétiques, la limite Barrémien-Aptien est marquée par la transition du Schrattenkalk inférieur, caractérisé par des carbonates photozaires, au Membre de Rawil caractérisé par des carbonates héterozoaires. Cette transition est marquée par une arrivée massive d'éléments détritiques et un apport de nutriments ayant entraîné la prolifération de foraminifères agglutinés tels que les orbitolines. L'analyse des minéraux argileux indique l'apparition de la kaolinite durant le Membre de Rawil, interprétée comme l'installation d'un climat plus chaud et humide. Un pic négatif en 513C est enregistré au sommet du Schrattenkalk inférieur correspond à l'excursion négative de -1%0 bien connue en domaine pélagique et datée comme Barrémien terminal. Cette corrélation apporte un contrôle chronostratigraphique supplémentaire permettant de dater le Schrattenkalk inférieur du Barrémien sup. et le Membre de Rawil de l'Aptien inf. D'autre part, une étude stratigraphique, basée sur des observations de terrain et sur l'interprétation d'assemblages floristiques et faunistiques en terme de paléoenvironnement a permis de mettre en évidence une limite de séquence au sommet du Schrattenkalk inf., corrélable avec la SbAl définie dans le Vercors. Durant la mise en place du Membre de Rawil, l'évolution des microfaciès est interprétée comme le « Transgressive System Tract » de la première séquence aptienne.En domaine pélagique, de minces couches riches en matière organique (MO) apparaissent dès le Barrémien sup. dans la coupe de Gorgo a Cerbara (Italie). Elles sont associées à un ratio C:P élevé indiquant des conditions épisodiquement dysoxiques à anoxiques. De plus, une corrélation nette entre Carbone Organique Total (TOC), phosphore (P) et silice biogénique est observée correspondant à un lien entre Ρ disponible, productivité et préservation de la MO. Pourtant, dans le même temps, le ÔI3C et le δ1βΟ restent constants indiquant des conditions environnementales stables et un cycle du carbone non perturbé par la préservation de MO qui ne serait pas la conséquence d'un changement climatique global mais juste d'un effet local.Ala limite Barrémien-Aptien, en domaine hémi-pélagique (La Bédoule, France) et pélagique (Gorgo a Cerbara), les couches riches en MO sont plus fréquentes et plus épaisses, elles se sont déposées en même temps qu'un pic négatif en 513CCARB et ô13Coib probablement dû à un épisode volcanique. A l'Aptien inf. le TOC des niveaux riches en MO augmente progressivement en même temps que la teneur en éléments traces jusqu'au dernier enrichissement avant l'événement anoxique océanique la (OAE la) correspondant au « niveau critique inf. », indiquant des conditions anoxiques moins restreintes. Celui-ci est également caractérisé par le fameux pic négatif en Ô13C (C3), une diminution du δ180 interprétée comme un réchauffement, par un pic en Ρ et un ratio C:P élevé. L'OAE 1 a, quant à lui, enregistre un refroidissement et coïncide avec le maximum en éléments traces ainsi qu'un fort ratio C:P mettant en valeur l'importance des conditions anoxiques pendant 1ΌΑΕ la dans cette coupe alors qu'aucune perturbation n'est enregistrés à La Bédoule probablement à cause de conditions paléogéographiques locales.Durant l'Aptien inf., les changements environnementaux sur la plate-forme se marquent par la prolifération d'orbitolines due à un changement climatique et une hausse du niveau marin. En domaine profond, la succession de niveaux riches en MO du Barrémien sup. jusqu'à l'OAE la documente l'impact progressif de changements paléoenvironnementaux, probablement liés à la formation du plateau d'Ontong Java à l'ouest de l'océan Pacifique.

Resigned but satisfied: The negative impact of public service motivation and red tape on work satisfaction

This article examines the relationship between red tape, Public Service Motivation (PSM) and a particular work outcome labelled 'resigned satisfaction'. Using data from a national survey of over 3754 public servants working at the municipal level in Switzerland, this study shows the importance of looking more closely at the concept of work satisfaction and, furthermore, of thoroughly investigating the impact of the different PSM dimensions on work outcomes. Unsurprisingly, research findings show that red tape is the most important predictor of resignation. Nevertheless, when PSM dimensions are analysed separately, results demonstrate that 'commitment to public interest/civic duty' and, to a lesser extent, 'attraction to policy-making' decrease resignation, whereas 'compassion' and 'self-sacrifice' increase it. This study thus highlights some of the negative (or undesirable) effects of PSM that have not been previously addressed in PSM literature.

Metallogenic model of the Trepca Pb-Zn-Ag skarn deposit, Kosovo: Evidence from fluid inclusions, Rare Earth Elements, and stable isotope data

The Trepca Pb-Zn-Ag skarn deposit (29 Mt of ore at 3.45% Pb, 2.30% Zn, and 80 g/t Ag) is located in the Kopaonik block of the western Vardar zone, Kosovo. The mineralization, hosted by recrystallized limestone of Upper Triassic age, was structurally and lithologically controlled. Ore deposition is spatially and temporally related with the postcollisional magmatism of Oligocene age (23-26 Ma). The deposit was formed during two distinct mineralization stages: an early prograde closed-system and a later retrograde open-system stage. The prograde mineralization consisting mainly of pyroxenes (Hd(54-100)Jo(0-45)Di(0-45)) resulted from the interaction of magmatic fluids associated with Oligocene (23-26 Ma) postcollisional magmatism. Whereas there is no direct contact between magmatic rocks and the mineralization, the deposit is classified as a distal Pb-Zn-Ag skarn. Abundant pyroxene reflects low oxygen fugacity (<10(-31) bar) and anhydrous environment. Fluid inclusion data and mineral assemblage limit the prograde stage within a temperature range between 390 degrees and 475 degrees C. Formation pressure is estimated below 900 bars. Isotopic composition of aqueous fluid, inclusions hosted by hedenbergite (delta D = -108 to -130 parts per thousand; delta O-18 = 7.5-8.0 parts per thousand), Mn-enriched mineralogy and high REE content of the host carbonates at the contact with the skarn mineralization suggest that a magmatic fluid was modified during its infiltration through the country rocks. The retrograde mineral assemblage comprises ilvaite, magnetite, arsenopyrite, pyrrhotite, marcasite, pyrite, quartz, and various carbonates. Increases in oxygen and sulfur fugacities, as well as a hydrous character of mineralization, require an open-system model. The opening of the system is related to phreatomagmatic explosion and formation of the breccia. Arsenopyrite geothermometer limits the retrograde stage within the temperature range between 350 degrees and 380 degrees C and sulfur fugacity between 10(-8.8) and 10(-7.2) bars. The principal ore minerals, galena, sphalerite, pyrite, and minor chalcopyrite, were deposited from a moderately saline Ca-Na chloride fluid at around 350 degrees C. According to the isotopic composition of fluid inclusions hosted by sphalerite (delta D = -55 to -74 parts per thousand; delta O-18 = -9.6 to -13.6 parts per thousand), the fluid responsible for ore deposition was dominantly meteoric in origin. The delta S-31 values of the sulfides spanning between -5.5 and +10 parts per thousand point to a magmatic origin of sulfur. Ore deposition appears to have been largely contemporaneous with the retrograde stage of the skarn development. Postore stage accompanied the precipitation of significant amount of carbonates including the travertine deposits at the deposit surface. Mineralogical composition of travertine varies from calcite to siderite and all carbonates contain significant amounts of Mn. Decreased formation temperature and depletion in the REE content point to an influence of pH-neutralized cold ground water and dying magmatic system.

Generation and function of mouse central memory and effector memory T cells

1. SUMMARY Based on functional and homing properties, two subsets of memory T lymphocytes have been defined both in humans and in mice. Central memory T cells (TCM cells) express the lymph node homing receptors CD62L and CCR7, have poor effector function and proliferate efficiently upon antigenic stimulation. Effector memory T cells (TEM cells) do not express CCR7, are mostly CD62L negative and therefore are excluded from lymph nodes, but are able to migrate to sites of inflammation where they exert immediate effector function by producing inflammatory cytokines and cytotoxic mediators. In the present work we have addressed two questions that emerged since the definition of TCM and TEM cells. Firstly, what are the priming conditions for generation of TCM and TEM and, secondly, what is the migratory capacity of TCM and TEM cells in inflammatory conditions. By using naive TCR-transgenic OT-I CD8+ T cells and OT-II CD4+ T cells and ovalbumin pulsed-mature dendritic cells (DCs) we set up an in vitro system in which the strength of T cell stimulation is controlled by varying the ratio of T cells and DCs and the duration of DC-T cell interaction. Using this system we found that precursors of TCM and TEM cells are generated at different strength of stimulation and that T cells capable of persisting in vivo in the absence of antigen and of mounting recall responses is optimally induced by intermediate stimulatory strength. In addition, we found that lymph nodes draining sites of mature DC or adjuvant inoculation recruit CD8+ CD62L- CCR7- effector and TEM cells. CD8+ T cell recruitment in reactive lymph nodes requires CXCR3 expression on T cells and occurs through high endothelial venules (HEVs) in concert with HEV lurninal expression of the CXCR3 ligand CXCL9. In reactive lymph nodes, recruited T cells establish stable interactions with and kill antigen-bearing DCs, limiting the ability of these DCs to activate CD4+ and CD8+ T cells. Taken togther these data define conditions for the generation of TCM and TEM cells and define an inflammatory pathway of effector T cell migration in lymph nodes. The inducible recruitment of blood-borne effector and TEM CD8+ cells to lymph nodes may represent a mechanism for terminating primary and limiting secondary immune responses.

Are 10 min of seating enough to guarantee stable haemoglobin and haematocrit readings for the athlete's biological passport?

Haemoglobin (Hb) and haematocrit (Hct) are measured as indirect markers of doping in athletes. We studied the effect of posture on these parameters in a typical antidoping setting. Venous blood samples were obtained from nine endurance athletes (six males, three females) and nine control subjects (six males, three females) immediately and after 5, 10, 15, 20 and 30 min after having adopted a seated position from normal daily activity. Hb (CV 0.72%) and Hct (CV 0.87%) were determined using an automated cell counter, plasma volume changes were calculated. Differences between the time points, gender and groups were calculated using a mixed-model procedure. Significant changes were observed in the first 10 min after sitting down but no further changes were noted between 10 and 30 min. Mean directional change for Hb and Hct between 0 min and the average of the period from 10 to 30 min was -2.4% (-0.35 g/dl) for Hb and -2.7% (-1.2%) for Hct. Plasma volume increased accordingly. Neither group nor gender had significant effects. Under typical conditions encountered during blood testing in doping control, a period of 10 min in a seated position is sufficient for the vascular volumes to re-equilibrate and to adapt to the new posture.

Plaque characteristics and arterial remodeling in coronary and peripheral arterial systems.

BACKGROUND: Few studies have examined plaque characteristics among multiple arterial beds in vivo. The purpose of this study was to compare the plaque morphology and arterial remodeling between coronary and peripheral arteries using gray-scale and radiofrequency intravascular ultrasound (IVUS) at clinical presentation. METHODS AND RESULTS: IVUS imaging was performed in 68 patients with coronary and 93 with peripheral artery lesions (29 carotid, 50 renal, and 14 iliac arteries). Plaques were classified as fibroatheroma (VH-FA) (further subclassified as thin-capped [VH-TCFA] and thick-capped [VH-ThCFA]), fibrocalcific plaque (VH-FC) and pathological intimal thickening (VH-PIT). Plaque rupture (13% of coronary, 7% of carotid, 6% of renal, and 7% of iliac arteries; P = NS) and VH-TCFA (37% of coronary, 24% of carotid, 16% of renal, and 7% of iliac arteries; P = 0.02) were observed in all arteries. Compared with coronary arteries, VH-FA was less frequently observed in renal (P < 0.001) and iliac arteries (P < 0.006). Lesions with positive remodeling demonstrated more characteristics of VH-FA in coronary (84% vs. 25%, P < 0.001), carotid (72% vs. 20%, P = 0.001), and renal arteries (42% vs. 4%, P = 0.001) compared with those with intermediate/negative remodeling. There was positive relationship between remodeling index and percent necrotic area in all four arteries. CONCLUSIONS: Atherosclerotic plaque phenotypes were heterogeneous among four different arteries; renal and iliac arteries had more stable phenotypes compared with coronary artery. In contrast, the associations of remodeling pattern with plaque phenotype and composition were similar among the various arterial beds.

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.

Le cancer du sein sans envahissement ganglionnaire. Au-delà des consensus internationaux: une approche pragmatique [Node negative breast cancer. Beyond international consensus: a pragmatic approach].

Apart from therapeutic advances related to new treatments, our practices in the management of early breast cancer have been modified by to key organizational settings (1) mass screening, substantially altering the presentation and epidemiology of breast cancer and (2) the development of guidelines to ensure that any patient management is in agreement with the demonstrated impact in the adjuvant treatment. In daily practice, the impact of screening and guidelines recommendations has put us now in a paradoxical situation: while the majority of non-metastatic breast cancers treated in the hexagon are node negative, most of the results of clinical studies on chemotherapy and targeted therapies today arise from populations predominantly node positive. Therefore, it seemed legitimate to convene a working group around a reflection on the directions of adjuvant chemotherapy in a growing node negative population in order to better respond to the questions of the field oncologists, trying to address the discrepancies between different existing guidelines.

Regulatory roles of the GacS/GacA two-component system in plant-associated and other gram-negative bacteria.

The sensor kinase GacS and the response regulator GacA are members of a two-component system that is present in a wide variety of gram-negative bacteria and has been studied mainly in enteric bacteria and fluorescent pseudomonads. The GacS/GacA system controls the production of secondary metabolites and extracellular enzymes involved in pathogenicity to plants and animals, biocontrol of soilborne plant diseases, ecological fitness, or tolerance to stress. A current model proposes that GacS senses a still-unknown signal and activates, via a phosphorelay mechanism, the GacA transcription regulator, which in turn triggers the expression of target genes. The GacS protein belongs to the unorthodox sensor kinases, characterized by an autophosphorylation, a receiver, and an output domain. The periplasmic loop domain of GacS is poorly conserved in diverse bacteria. Thus, a common signal interacting with this domain would be unexpected. Based on a comparison with the transcriptional regulator NarL, a secondary structure can be predicted for the GacA sensor kinases. Certain genes whose expression is regulated by the GacS/GacA system are regulated in parallel by the small RNA binding protein RsmA (CsrA) at a posttranscriptional level. It is suggested that the GacS/GacA system operates a switch between primary and secondary metabolism, with a major involvement of posttranscriptional control mechanisms.