Yersinia pestis Endowed with Increased Cytotoxicity Is Avirulent in a Bubonic Plague Model and Induces Rapid Protection against Pneumonic Plague

An important virulence strategy evolved by bacterial pathogens to overcome host defenses is the modulation of host cell death. Previous observations have indicated that Yersinia pestis, the causative agent of plague disease, exhibits restricted capacity to induce cell death in macrophages due to ineffective translocation of the type III secretion effector YopJ, as opposed to the readily translocated YopP, the YopJ homologue of the enteropathogen Yersinia enterocolitica O∶8. This led us to suggest that reduced cytotoxic potency may allow pathogen propagation within a shielded niche, leading to increased virulence. To test the relationship between cytotoxic potential and virulence, we replaced Y. pestis YopJ with YopP. The YopP-expressing Y. pestis strain exhibited high cytotoxic activity against macrophages in vitro. Following subcutaneous infection, this strain had reduced ability to colonize internal organs, was unable to induce septicemia and exhibited at least a 107-fold reduction in virulence. Yet, upon intravenous or intranasal infection, it was still as virulent as the wild-type strain. The subcutaneous administration of the cytotoxic Y. pestis strain appears to activate a rapid and potent systemic, CTL-independent, immunoprotective response, allowing the organism to overcome simultaneous coinfection with 10,000 LD50 of virulent Y. pestis. Moreover, three days after subcutaneous administration of this strain, animals were also protected against septicemic or primary pneumonic plague. Our findings indicate that an inverse relationship exists between the cytotoxic potential of Y. pestis and its virulence following subcutaneous infection. This appears to be associated with the ability of the engineered cytotoxic Y. pestis strain to induce very rapid, effective and long-lasting protection against bubonic and pneumonic plague. These observations have novel implications for the development of vaccines/therapies against Y. pestis and shed new light on the virulence strategies of Y. pestis in nature

Hydrodynamical Simulations of Galaxy Clusters with Galcons

We present our recently developed {\em galcon} approach to hydrodynamical cosmological simulations of galaxy clusters - a subgrid model added to the {\em Enzo} adaptive mesh refinement code - which is capable of tracking galaxies within the cluster potential and following the feedback of their main baryonic processes. Galcons are physically extended galactic constructs within which baryonic processes are modeled analytically. By identifying galaxy halos and initializing galcons at high redshift ($z \sim 3$, well before most clusters virialize), we are able to follow the evolution of star formation, galactic winds, and ram-pressure stripping of interstellar media, along with their associated mass, metals and energy feedback into intracluster (IC) gas, which are deposited through a well-resolved spherical interface layer. Our approach is fully described and all results from initial simulations with the enhanced {\em Enzo-Galcon} code are presented. With a galactic star formation rate derived from the observed cosmic star formation density, our galcon simulation better reproduces the observed properties of IC gas, including the density, temperature, metallicity, and entropy profiles. By following the impact of a large number of galaxies on IC gas we explicitly demonstrate the advantages of this approach in producing a lower stellar fraction, a larger gas core radius, an isothermal temperature profile in the central cluster region, and a flatter metallicity gradient than in a standard simulation

Clinical management of borderline tumours of the ovary: results of a multicentre survey of 323 clinics in Germany

The aim of this survey was to analyse the standard of care in diagnostic, surgery, chemotherapy and aftercare management for patients with borderline tumours of the ovary (BOTs) in Germany. A structured questionnaire comprising different dimensions was sent to all 1114 gynaecological departments. The questionnaire could be returned anonymously. The overall response rate was 29.0% (323 departments). Most departments were on secondary care (71.8%), tertiary care (23.2%) or university hospital (5.0%) level. Most clinicians performed not more than five BOT operations (89.2%) per year. Most departments (93.2%) used in addition to classical bimanual examination and vaginal ultrasound, tumour marker CA-125 detection, CT scan, MRI or PET-CT techniques. Departments in university and tertiary care hospitals performed more often a fresh frozen section (87 vs 64%). In young women, clinicians performed much seldom unilateral salpingo-oophorectomy (92%) and only in 53% biopsies of the contralateral ovary. Generally, biopsies of the contralateral ovary were performed in 4–53% of the patients. Chemotherapy was mostly favoured in ‘high-risk' patients with tumour residual, microinvasion or invasive implants. Thus, a high grade of insecurity in diagnostic and therapy of BOT exists in some gynaecological departments and underlines the need for more educational and study activities

The NlpD Lipoprotein Is a Novel Yersinia pestis Virulence Factor Essential for the Development of Plague

Yersinia pestis is the causative agent of plague. Previously we have isolated an attenuated Y. pestis transposon insertion mutant in which the pcm gene was disrupted. In the present study, we investigated the expression and the role of pcm locus genes in Y. pestis pathogenesis using a set of isogenic surE, pcm, nlpD and rpoS mutants of the fully virulent Kimberley53 strain. We show that in Y. pestis, nlpD expression is controlled from elements residing within the upstream genes surE and pcm. The NlpD lipoprotein is the only factor encoded from the pcm locus that is essential for Y. pestis virulence. A chromosomal deletion of the nlpD gene sequence resulted in a drastic reduction in virulence to an LD50 of at least 107 cfu for subcutaneous and airway routes of infection. The mutant was unable to colonize mouse organs following infection. The filamented morphology of the nlpD mutant indicates that NlpD is involved in cell separation; however, deletion of nlpD did not affect in vitro growth rate. Trans-complementation experiments with the Y. pestis nlpD gene restored virulence and all other phenotypic defects. Finally, we demonstrated that subcutaneous administration of the nlpD mutant could protect animals against bubonic and primary pneumonic plague. Taken together, these results demonstrate that Y. pestis NlpD is a novel virulence factor essential for the development of bubonic and pneumonic plague. Further, the nlpD mutant is superior to the EV76 prototype live vaccine strain in immunogenicity and in conferring effective protective immunity. Thus it could serve as a basis for a very potent live vaccine against bubonic and pneumonic plague

Nitrate radicals and biogenic volatile organic compounds: oxidation, mechanisms, and organic aerosol

Oxidation of biogenic volatile organic compounds (BVOC) by the nitrate radical (NO_3) represents one of the important interactions between anthropogenic emissions related to combustion and natural emissions from the biosphere. This interaction has been recognized for more than 3 decades, during which time a large body of research has emerged from laboratory, field, and modeling studies. NO_3-BVOC reactions influence air quality, climate and visibility through regional and global budgets for reactive nitrogen (particularly organic nitrates), ozone, and organic aerosol. Despite its long history of research and the significance of this topic in atmospheric chemistry, a number of important uncertainties remain. These include an incomplete understanding of the rates, mechanisms, and organic aerosol yields for NO_3-BVOC reactions, lack of constraints on the role of heterogeneous oxidative processes associated with the NO_3 radical, the difficulty of characterizing the spatial distributions of BVOC and NO_3 within the poorly mixed nocturnal atmosphere, and the challenge of constructing appropriate boundary layer schemes and non-photochemical mechanisms for use in state-of-the-art chemical transport and chemistry–climate models. This review is the result of a workshop of the same title held at the Georgia Institute of Technology in June 2015. The first half of the review summarizes the current literature on NO_3-BVOC chemistry, with a particular focus on recent advances in instrumentation and models, and in organic nitrate and secondary organic aerosol (SOA) formation chemistry. Building on this current understanding, the second half of the review outlines impacts of NO_3-BVOC chemistry on air quality and climate, and suggests critical research needs to better constrain this interaction to improve the predictive capabilities of atmospheric models

Demographic Aspects of Irregular Immigrants in Israel

Euro-Mediterranean Consortium for Applied Research on International Migration (CARIM)This paper focuses on traditional groups of irregular migrants in Israel, especially the various types of unauthorized labor migrants, and to a lesser extent on refugees. Estimates for the sizes of the various groups of unauthorized labor migrants – Palestinians from the Occupied Territories and unauthorized labor migrants from overseas – have been presented using diverse sources and calculations. Their demographic characteristics, mostly age and sex, as well as trends regarding their economic impact on the Israeli economy and deportations have been developed in a concluding part

Size and Selectivity Patterns among Israeli Born Immigrants in OECD Countries

Euro-Mediterranean Consortium for Applied Research on International Migration (CARIM)Abstract In recent years, there has been much concern about the size and selectivity of the Israeli emigrant population. This paper focuses on two issues regarding Israeli emigrants. First, it focuses on their number and distribution in various destination countries; while the second part of the paper deals with patterns of self-selection among emigrants, namely, the skill level of Israelis who select themselves to leave Israel for various destination countries. The paper addresses these issues using the DIOC (Database on Immigrants in OECD Countries) which includes information on the foreign born (including Israeli-born) from censuses and population registers in OECD countries. The findings suggest that Israeli emigration has increased in the past two decades, but that most of the increase was in the 1990s, and was due to the emigration of foreign-born Israelis, rather than the emigration of native-born Israelis. Based on the DIOC, 164,000 Israeli-born emigrants, aged 15 years and over, resided in 25 OECD countries in 2000. Two thirds of the emigrants were in the US, and 85% in the Anglo-Saxon countries (the US, Canada, UK, Australia, New Zealand and Ireland). France is the only non Anglo-Saxon country where over 5,000 Israelis resided. Based on Israeli and American sources, this paper also presents estimates for the total size of the Israeli-born emigrant population (including children under 15 and including non-OECD countries), as well as estimates for the number of foreign-born Israeli emigrants from Israel. The selectivity of Israeli emigrants, measured by education, occupation, employment status, and age is most positive in the Anglo-Saxon countries, especially the US, where the returns on skills are the highest. By contrast, the least skilled Israeli emigrants choose Scandinavian countries, where the labor markets are relatively rigid, and returns on skills tend to be the lowest. Selectivity for other European countries is somewhere in the middle, but the emerging, unregulated and unequal economies of Eastern Europe appear to attract very few, albeit highly-skilled, Israelis. These findings are consistent with migration selectivity theory which anticipates that high-skilled immigrants will choose destinations where their skills will be generously compensated. Additional support for the hypothesis that the skilled choose destinations with higher returns on skills, is evident from an analysis of very high skilled Israeli-born emigrants, those holding a Ph.D. degree or its equivalent. There are at least 5,600 such emigrants in OECD countries, and about 75% of them reside in the US. In the Anglo-Saxon countries (but not in continental Europe) about 40% of them are employed in colleges and universities. While only 7% of those with a Ph.D. in the US and other Anglo-Saxon countries do not work, the respective proportion in Europe is much higher, implying that the unobserved skills of many Israeli Ph.D.s in Europe are not as high as their (observed) high educational degree. Put differently, the unobserved skills of highly-educated Israeli emigrants are more positive in the US and Anglo-Saxon countries than in Europe. Finally, the relationship between selectivity and returns to skills are also demonstrated in correlations between labor market characteristics and immigrant skills. Résumé Le volume et la sélectivité de la population émigrante d’Israël ont connu un gain d’intérêt ces dernières années. Ce papier focalise sur deux problématiques concernant les émigrés israéliens. D’abord, il présente leurs effectifs et distribution dans divers pays de destination. Ensuite, il traite des modes d’auto sélection parmi les émigrants ; c’est-à-dire du niveau de qualification des israéliens qui se sélectionnent eux-mêmes pour quitter Israël et se diriger vers divers pays de destination. Le papier aborde la question en utilisant la base de données sur les immigrés dans les pays de l’OCDE (Database on Immigrants in OECD countries, DIOC) qui contient les informations sur les personnes nés à l’étranger (y compris les natifs d’Israël), extraites des recensements et des registres de population dans les pays OCDE. Les données montrent que le volume de l’émigration israélienne a augmenté pendant les deux dernières décennies, surtout au cours des années 1990, et que cette émigration est plus le fait des israéliens nés en dehors d’Israël que des israéliens nés en Israël. Selon la base de données DIOC, 164.000 émigrés natifs d’Israël, âgés de 15 ans et plus, résident dans 25 pays OCDE en 2000. Deux tiers des émigrés étaient aux Etats Unis et 85% dans les pays anglo-saxons (Etats-Unis, Canada, Royaume-Uni, Nouvelle-Zélande et Irlande). La France est le seul pays non anglo-saxon où résident 5.000 israéliens. En se basant sur des sources israéliennes et américaines, ce papier présente aussi des estimations de l’effectif total de la population émigrée native d’Israël (y compris les moins de 15 ans et les non-résidents dans les pays OCDE) ainsi que des estimations de l’effectif des émigrés israéliens nés en dehors d’Israël. La sélectivité des émigrés israéliens, mesurée par l’éducation, la profession, la situation dans la profession et l’âge, est la plus positive dans les pays anglo-saxons, notamment les Etats-Unis, où les récompenses des compétences sont élevées. A l’opposé, les moins qualifiés des émigrés israéliens optent pour les pays scandinaves, où les marchés du travail sont relativement rigides et les récompenses des qualifications comptent parmi les plus basses. La sélectivité pour les autres pays européens se situe quelque part entre les deux, mais l’émergence d’économies non régulés et inégalitaires en Europe de l’Est semble attirer très peu de migrants israéliens qui, toutefois, disposent de très hautes qualifications. Ce résultat est compatible avec la théorie de la sélectivité de la migration qui prévoit que les migrants hautement qualifiés choisissent les destinations où leurs qualifications seront généreusement récompensées. Un autre appui pour l’hypothèse selon laquelle les qualifiés optent pour les destinations avec des récompenses élevées pour les compétences est mis en évidence à partir de l’analyse d’émigrants très hautement qualifiés natifs d’Israël, notamment ceux qui disposent d’un niveau Ph.D. ou équivalent. Il y a au moins 5.600 émigrants du genre dans les pays OCDE dont environ 75% aux Etats-Unis. Dans les pays anglo-saxons (mais pas l’Europe continentale), près de 40% d’entre eux sont employés dans des instituts supérieurs et universités. Au même temps, seulement 7% de ceux disposant d’un Ph.D. et résidant aux Etats-Unis et autres pays anglo-saxons ne travaillent pas. Cette proportion est beaucoup plus élevée en Europe impliquant que les qualifications non observées de la plupart des détenteurs d’un Ph.D. en Europe ne sont pas aussi élevées que leur haut niveau d’éducation (observé). Autrement dit, les qualifications non observées des émigrés israéliens disposant d’un haut niveau d’éducation sont plus positives aux Etats-Unis qu’en Europe. Finalement, la relation entre sélectivité et récompenses pour compétences a été aussi démontrée dans les corrélations entre les caractéristiques du marché du travail et les compétences des migrants

Circular Migration in Israell: Demographic and Economic Aspects

Euro-Mediterranean Consortium for Applied Research on International Migration (CARIM