Clostridium perfringens Epsilon Toxin Targets Granule Cells in the Mouse Cerebellum and Stimulates Glutamate Release

Epsilon toxin (ET) produced by C. perfringens types B and D is a highly potent pore-forming toxin. ET-intoxicated animals express severe neurological disorders that are thought to result from the formation of vasogenic brain edemas and indirect neuronal excitotoxicity. The cerebellum is a predilection site for ET damage. ET has been proposed to bind to glial cells such as astrocytes and oligodendrocytes. However, the possibility that ET binds and attacks the neurons remains an open question. Using specific anti-ET mouse polyclonal antibodies and mouse brain slices preincubated with ET, we found that several brain structures were labeled, the cerebellum being a prominent one. In cerebellar slices, we analyzed the co-staining of ET with specific cell markers, and found that ET binds to the cell body of granule cells, oligodendrocytes, but not astrocytes or nerve endings. Identification of granule cells as neuronal ET targets was confirmed by the observation that ET induced intracellular Ca2+ rises and glutamate release in primary cultures of granule cells. In cultured cerebellar slices, whole cell patch-clamp recordings of synaptic currents in Purkinje cells revealed that ET greatly stimulates both spontaneous excitatory and inhibitory activities. However, pharmacological dissection of these effects indicated that they were only a result of an increased granule cell firing activity and did not involve a direct action of the toxin on glutamatergic nerve terminals or inhibitory interneurons. Patch-clamp recordings of granule cell somata showed that ET causes a decrease in neuronal membrane resistance associated with pore-opening and depolarization of the neuronal membrane, which subsequently lead to the firing of the neuronal network and stimulation of glutamate release. This work demonstrates that a subset of neurons can be directly targeted by ET, suggesting that part of ET-induced neuronal damage observed in neuronal tissue is due to a direct effect of ET on neurons

GALEX UV Color Relations for Nearby Early-Type Galaxies

We use GALEX/optical photometry to construct color-color relationships for early-type galaxies sorted by morphological type. We have matched objects in the GALEX GR1 public release and the first IR1.1 internal release, with the RC3 early-type galaxies having a morphological type -5.5<T<-1.5 with mean error in T<1.5, and mean error on (B-V)T<0.05. After visual inspection of each match, we are left with 130 galaxies with a reliable GALEX pipeline photometry in the far-UV and near-UV bands. This sample is divided into Ellipticals (-5.5<T<-3.5) and Lenticulars (-3.5<T<-1.5). After correction for the Galactic extinction, the color-color diagrams FUV-NUV vs. (B-V)_{Tc} are plotted for the two subsamples. We find a tight anti-correlation between the FUV-NUV and (B-V)_{Tc} colors for Ellipticals, the UV color getting bluer when the (B-V)_{Tc} get redder. This relationship very likely is an extension of the color-metallicity relationship into the GALEX NUV band. We suspect that the main source of the correlation is metal line blanketing in the NUV band. The FUV-NUV vs B-V correlation has larger scatter for lenticular galaxies; we speculate this reflects the presence of low level star formation. If the latter objects (i.e. those that are blue both in FUV-NUV and B-V) are interpreted as harboring recent star formation activity, this would be the case for a few percent (~4%) of Ellipticals and ~15% of Lenticulars; this would make about 10% of early-type galaxies with residual star formation in our full sample of 130 early-type galaxies. We also plot FUV-NUV vs. the Mg_2 index and central velocity dispersion. We find a tight anti-correlation between FUV-NUV and the Mg_2 index(...).Comment: 25 pages, 5 figures, accepted for publication in ApJS (abstract abridged), typos corrected in section 2.

Training for impact : the socio-economic impact of a fit for purpose health workforce on communities

Across the globe, a "fit for purpose" health professional workforce is needed to meet health needs and challenges while capitalizing on existing resources and strengths of communities. However, the socio-economic impact of educating and deploying a fit for purpose health workforce can be challenging to evaluate. In this paper, we provide a brief overview of six promising strategies and interventions that provide context-relevant health professional education within the health system. The strategies focused on in the paper are:1. Distributed community-engaged learning: Education occurs in or near underserved communities using a variety of educational modalities including distance learning. Communities served provide input into and actively participate in the education process.2. Curriculum aligned with health needs: The health and social needs of targeted communities guide education, research and service programmes.3. Fit for purpose workers: Education and career tracks are designed to meet the needs of the communities served. This includes cadres such as community health workers, accelerated medically trained clinicians and extended generalists.4. Gender and social empowerment: Ensuring a diverse workforce that includes women having equal opportunity in education and are supported in their delivery of health services.5. Interprofessional training: Teaching the knowledge, skills and attitudes for working in effective teams across professions.6. South-south and north-south partnerships: Sharing of best practices and resources within and between countries.In sum, the sharing of resources, the development of a diverse and interprofessional workforce, the advancement of primary care and a strong community focus all contribute to a world where transformational education improves community health and maximizes the social and economic return on investment

Effects of Low Amyloid-β (Aβ) Concentration on Aβ1-42 Oligomers Binding and GluN2B Membrane Expression.

Numerous studies have shown that amyloid-β (Aβ) modulate intracellular metabolic cascades and an intracellular Ca2+ homeostasis and a cell surface NMDA receptor expression alteration in Alzheimer's disease (AD). However most of these findings have been obtained by using non-physiological Aβ concentrations. The present study deals with the effect of low Aβ concentrations on cellular homeostasis. We used nerve growth factor-differentiated PC12 cells and murine cortical neurons sequentially treated with low chronic monomeric or small oligomeric Aβ concentrations and high acute oligomeric Aβ concentrations to bring out a priming effect of chronic treatment on subsequently high Aβ concentrations-elicited cellular response. Both cell types indeed displayed an enhanced capacity to bind oligomeric Aβ after monomeric or small oligomeric Aβ application. Furthermore, the results show that monomeric Aβ1-42 application to the cells induces an increase of the Ca2+-response and of the membrane expression of the extrasynaptic subunit of the NMDA receptor GluN2B in PC12 cells, while the opposite effects were observed in cultured neurons. This suggests a sequential interaction of Aβ with the cellular plasma membrane involving monomers or small Aβ oligomers which would facilitate the binding of the deleterious high molecular Aβ oligomers. This mechanism would explain the slow progression of AD in the human nervous system and the deep gradient of neuronal death observed around the amyloid plaques in the nervous tissue.journal articleresearch support, non-u.s. gov't2015importe

The Look-back Time Evolution of Far-Ultraviolet Flux from the Brightest Cluster Elliptical Galaxies at z < 0.2

We present the GALEX UV photometry of the elliptical galaxies in Abell clusters at moderate redshifts (z < 0.2) for the study of the look-back time evolution of the UV upturn phenomenon. The brightest elliptical galaxies (M_r < -22) in 12 remote clusters are compared with the nearby giant elliptical galaxies of comparable optical luminosity in the Fornax and Virgo clusters. The sample galaxies presented here appear to be quiescent without signs of massive star formation or strong nuclear activity, and show smooth, extended profiles in their UV images indicating that the far-UV (FUV) light is mostly produced by hot stars in the underlying old stellar population. Compared to their counterparts in nearby clusters, the FUV flux of cluster giant elliptical galaxies at moderate redshifts fades rapidly with ~ 2 Gyrs of look-back time, and the observed pace in FUV - V color evolution agrees reasonably well with the prediction from the population synthesis models where the dominant FUV source is hot horizontal-branch stars and their progeny. A similar amount of color spread (~ 1 mag) in FUV - V exists among the brightest cluster elliptical galaxies at z ~ 0.1, as observed among the nearby giant elliptical galaxies of comparable optical luminosity.Comment: Accepted for publication in the Special GALEX ApJ Supplement, December 200

Preliminary inventory of fruit fly species (Diptera, Tephritidae) in mango orchards in the Niayes region, Senegal, in 2004

Introduction. Knowledge of tephritid diversity in Senegal was poor before 2004, so PIP-COLEACP and CIRAD, in collaboration with Cérès-DPV, carried out, in 2004, trapping for preliminary detection of fruit flies in six orchards in the Niayes zone. Materials and methods. We selected three mixed mango orchards and three homogeneous mango orchards in this zone. In each orchard, we used three attractants: Terpinyl acetate (Ter), Trimedlure (Tri) and Torula (Tor). Traps were serviced weekly. Results. We captured 77 642 fruit flies in more than 4 months including mango season; they were represented by 18 identified fly species, including ten Ceratitis, six Dacus and two Bactrocera species. Two very serious pests were identified with the confirmation of Bactrocera cucurbitae (Coquillett) for cucurbit crops and the detection of B. invadens Drew Tsuruta & White for fruit crops. The two most abundant species of Ceratitis were C. cosyra and C. silvestrii. Discussion. We captured more fruit fly specie s in mixed mango orchards than in homogeneous mango orchards. Bactrocera invadens was also more abundant in mixed orchards, probably because of its polyphagous status. This new invasive species, B. invadens , can have many hosts in mixed mango orchards , enhancing its breeding potential. Conclusion. Effective management to deal with this alien species requires: (i) improvement of basic and applied research; (ii) an effective IPM package; (iii) an area-wide management approach; (iv) a sub-regional effort on the part of researchers, extension services, growers, exporters, farming associations and the different actors in fruit value chains (mainly mango). (Résumé d'auteur

Adverse Cardiovascular Events Arising From Atherosclerotic Lesions With and Without Angiographic Disease Progression

ObjectivesThe aim of this study was to use angiography and grayscale and intravascular ultrasound–virtual histology to assess coronary lesions that caused events during a median follow-up period of 3.4 years.BackgroundVulnerable plaque-related events are assumed to be the result of substantial progression of insignificant lesions.MethodsIn the PROSPECT (Providing Regional Observations to Study Predictors of Events in the Coronary Tree) study, 697 patients with acute coronary syndromes underwent treatment of all culprit lesions followed by 3-vessel imaging to assess the natural history of culprit and untreated nonculprit (NC) lesions. Future adverse cardiovascular events adjudicated to NC lesions were divided into those with versus without substantial lesion progression (SLP) (≥20% angiographic diameter stenosis increase).ResultsNC lesion events occurred in 72 patients, 44 (61%) with and 28 (39%) without SLP. Myocardial infarctions (n = 6) occurred only in patients with SLP. Conversely, patients without SLP presented only with unstable or increasing angina requiring rehospitalization. Lesions with versus without SLP occurred later (median time to event 401 vs. 223 days, p = 0.07); were less severe at baseline (median diameter stenosis 26.4% vs. 53.8%, p < 0.0001) but more severe at the time of the event (mean diameter stenosis 73.8% vs. 56%, p < 0.0001); and had comparable baseline median plaque burden (68.7% vs. 70.1%, p = 0.17), minimum luminal area (3.7 vs. 4.0 mm2, p = 0.60), and intravascular ultrasound–virtual histology phenotype (83.3% vs. 90.9%, p = 0.68; classified as fibroatheromas at baseline).ConclusionsNC lesions responsible for future cardiovascular events showed angiographic increase during 3.4 years of follow-up, whereas SLP underlay many but not all of them. NC events due to lesions with SLP were angiographically less severe and presented with a delayed time course but were otherwise indistinguishable from NC events that were not associated with SLP

Combined MEK and PI3K/p110β Inhibition as a Novel Targeted Therapy for Malignant Mesothelioma Displaying Sarcomatoid Features

Among malignant mesotheliomas (MM), the sarcomatoid subtype is associated with higher chemoresistance and worst survival. Due to its low incidence, there has been little progress in the knowledge of the molecular mechanisms associated with sarcomatoid MM, which might help to define novel therapeutic targets. In this work, we show that loss of PTEN expression is frequent in human sarcomatoid MM and PTEN expression levels are lower in sarcomatoid MM than in the biphasic and epithelioid subtypes. Combined Pten and Trp53 deletion in mouse mesothelium led to nonepithelioid MM development. In Pten;Trp53-null mice developing MM, the Gαi2-coupled receptor subunit activated MEK/ERK and PI3K, resulting in aggressive, immune-suppressed tumors. Combined inhibition of MEK and p110β/PI3K reduced mouse tumor cell growth in vitro. Therapeutic inhibition of MEK and p110β/PI3K using selumetinib (AZD6244, ARRY-142886) and AZD8186, two drugs that are currently in clinical trials, increased the survival of Pten;Trp53-null mice without major toxicity. This drug combination effectively reduced the proliferation of primary cultures of human pleural (Pl) MM, implicating nonepithelioid histology and high vimentin, AKT1/2, and Gαi2 expression levels as predictive markers of response to combined MEK and p110β/PI3K inhibition. Our findings provide a rationale for the use of selumetinib and AZD8186 in patients with MM with sarcomatoid features. This constitutes a novel targeted therapy for a poor prognosis and frequently chemoresistant group of patients with MM, for whom therapeutic options are currently lacking.[Significance] Mesothelioma is highly aggressive; its sarcomatoid variants have worse prognosis. Building on a genetic mouse model, a novel combination therapy is uncovered that is relevant to human tumors.This work was supported, in part, by grants from Asociación Española Contra el Cáncer (F.X. Real), Spanish Ministry of Economy and Competitivity, Plan Estatal de I+D+I 2013-2016, ISCIII (FIS PI15/00045 to A. Carnero), RTICC (Instituto de Salud Carlos III, grants RD12/0036/0034 to F.X. Real and A. Carnero, respectively), and CIBERONC (CB16/12/00453 and CD16/12/00275 to F.X. Real and A. Carnero, respectively), cofunded by FEDER from Regional Development European Funds (European Union) and Inserm (Institut national de la santé et de la recherche médicale). M. Marqués was supported by a Sara Borrell Fellowship from Instituto de Salud Carlos III. CNIO is supported by Ministerio de Ciencia, Innovación y Universidades as a Centro de Excelencia Severo Ochoa SEV-2015-0510

Making science at home: visual displays of space science and nuclear physics at the Science Museum and on television in postwar Britain

The public presentation of science and technology in postwar Britain remains a field open to exploration. Current scholarship on the topic is growing but still tends to concentrate on the written word, thus making theorizing, at this stage, difficult. This paper is an attempt to expand the literature through two case studies that compare and synthesize displays of scientific and technological knowledge in two visual media, the Science Museum and television, in the 1950s and 1960s. The topics of these case studies are space exploration and nuclear energy. The thesis this paper explores is that both media fleshed out strategies of displays based on the use of categories from everyday life. As a result, outcomes of large-scale public scientific and technological undertakings were interwoven within audiences’ daily life experiences, thus appearing ordinary rather than extraordinary. This use of symbols and values drawn from private life worked to alleviate fears of risk associated with these new fields of technological exploration and at the same time give them widespread currency in the public sphere

Robot-assisted pelvic floor reconstructive surgery:an international Delphi study of expert users

Background: Robotic surgery has gained popularity for the reconstruction of pelvic floor defects. Nonetheless, there is no evidence that robot-assisted reconstructive surgery is either appropriate or superior to standard laparoscopy for the performance of pelvic floor reconstructive procedures or that it is sustainable. The aim of this project was to address the proper role of robotic pelvic floor reconstructive procedures using expert opinion. Methods: We set up an international, multidisciplinary group of 26 experts to participate in a Delphi process on robotics as applied to pelvic floor reconstructive surgery. The group comprised urogynecologists, urologists, and colorectal surgeons with long-term experience in the performance of pelvic floor reconstructive procedures and with the use of the robot, who were identified primarily based on peer-reviewed publications. Two rounds of the Delphi process were conducted. The first included 63 statements pertaining to surgeons’ characteristics, general questions, indications, surgical technique, and future-oriented questions. A second round including 20 statements was used to reassess those statements where borderline agreement was obtained during the first round. The final step consisted of a face-to-face meeting with all participants to present and discuss the results of the analysis. Results: The 26 experts agreed that robotics is a suitable indication for pelvic floor reconstructive surgery because of the significant technical advantages that it confers relative to standard laparoscopy. Experts considered these advantages particularly important for the execution of complex reconstructive procedures, although the benefits can be found also during less challenging cases. The experts considered the robot safe and effective for pelvic floor reconstruction and generally thought that the additional costs are offset by the increased surgical efficacy. Conclusion: Robotics is a suitable choice for pelvic reconstruction, but this Delphi initiative calls for more research to objectively assess the specific settings where robotic surgery would provide the most benefit.</p