Mutational Analysis of the Chlamydia muridarum Plasticity Zone

Pathogenically diverse Chlamydia spp. can have surprisingly similar genomes. C. trachomatis isolates that cause trachoma, sexually transmitted genital tract infections (chlamydia) and invasive lymphogranuloma venereum (LGV), and the murine strain C. muridarum share 99% of their gene content. A region of high genomic diversity between Chlamydia spp. termed the Plasticity Zone (PZ) may encode niche-specific virulence determinants that dictate pathogenic diversity. We hypothesized that PZ genes might mediate the greater virulence and IFN-γ resistance of C. muridarum compared to C. trachomatis in the murine genital tract. To test this hypothesis, we isolated and characterized a series of C. muridarum PZ nonsense mutants. Strains with nonsense mutations in chlamydial cytotoxins, guaBA-add and a phospholipase D homolog developed normally in cell culture. Two of the cytotoxin mutants were less cytotoxic than wild-type suggesting that the cytotoxins may be functional. However, none of the PZ nonsense mutants exhibited increased IFN-γ sensitivity in cell culture or were profoundly attenuated in a murine genital tract infection model. Our results suggest that C. muridarum PZ genes are transcribed and some may produce functional proteins, but are dispensable for infection of the murine genital tract

Classification and Prediction of Survival in Patients with the Leukemic Phase of Cutaneous T Cell Lymphoma

We have used cDNA arrays to investigate gene expression patterns in peripheral blood mononuclear cells from patients with leukemic forms of cutaneous T cell lymphoma, primarily Sezary syndrome (SS). When expression data for patients with high blood tumor burden (Sezary cells >60% of the lymphocytes) and healthy controls are compared by Student's t test, at P < 0.01, we find 385 genes to be differentially expressed. Highly overexpressed genes include Th2 cells–specific transcription factors Gata-3 and Jun B, as well as integrin β1, proteoglycan 2, the RhoB oncogene, and dual specificity phosphatase 1. Highly underexpressed genes include CD26, Stat-4, and the IL-1 receptors. Message for plastin-T, not normally expressed in lymphoid tissue, is detected only in patient samples and may provide a new marker for diagnosis. Using penalized discriminant analysis, we have identified a panel of eight genes that can distinguish SS in patients with as few as 5% circulating tumor cells. This suggests that, even in early disease, Sezary cells produce chemokines and cytokines that induce an expression profile in the peripheral blood distinctive to SS. Finally, we show that using 10 genes, we can identify a class of patients who will succumb within six months of sampling regardless of their tumor burden

A live-attenuated chlamydial vaccine protects against trachoma in nonhuman primates

In cynomolgus macaques, ocular infection with a live trachoma strain lacking the conserved 7.5-kb plasmid induced no ocular pathology but facilitated solid or partial protection from subsequent infection with a virulent strain of trachoma

ORAMA project deliverable 1.2. Final analysis and recommendations for the improvement of statistical data collection methods in Europe for primary raw materials

This report brings together the outputs of Task 1.1 and 1.2 of Work Package 1 of the ORAMA project. Task 1.1 aims to produce an inventory of how minerals data are collected within Europe, via a survey of data providers, and Task 1.2 aims to review previous work from past projects, working groups and professional organisations in this subject area. Together this has built a comprehensive understanding of how minerals data are collected in Europe, what data gaps exist, what the issues are with regard to creating harmonised European datasets for minerals information and what good practice examples exist that lessons can be learnt from. The results of the survey show that countries that have a clear legal and regulatory procedure for collecting data often have the most robust systems in place. These countries often also have a strong motivation for collecting such data, such as receiving a significant income from mineral royalties as a result of state ownership of minerals, although resource management or land use planning also provide motivation for the collection of data. The results of the survey also showed there is a large variety in the way data is collected within Europe. This variety is not necessarily an issue with regard harmonisation as long as data providers ensure that they adhere to common data standards and classification systems, such as INSPIRE or UNFC when providing data for aggregation at a European level. The review of previous projects showed the breadth of work that had gone into the improvement of statistical datasets over the last few years. Especially from projects such as Minventory and Minerals4EU, which provide a clear roadmap for harmonising European minerals datasets, or the work of the EGS MREG (EuroGeoSurveys Mineral Resources Expert Group) towards the harmonisation of resource and reserve codes within Europe. A common theme of many of these recommendations is the need for common standards to be adhered to and that in some instances these specifications may need to be adapted to accommodate statistical data for mineral resources which are aggregated at a national scale

Comprehensive global genome dynamics of Chlamydia trachomatis show ancient diversification followed by contemporary mixing and recent lineage expansion.

Chlamydia trachomatis is the world's most prevalent bacterial sexually transmitted infection and leading infectious cause of blindness, yet it is one of the least understood human pathogens, in part due to the difficulties of in vitro culturing and the lack of available tools for genetic manipulation. Genome sequencing has reinvigorated this field, shedding light on the contemporary history of this pathogen. Here, we analyze 563 full genomes, 455 of which are novel, to show that the history of the species comprises two phases, and conclude that the currently circulating lineages are the result of evolution in different genomic ecotypes. Temporal analysis indicates these lineages have recently expanded in the space of thousands of years, rather than the millions of years as previously thought, a finding that dramatically changes our understanding of this pathogen's history. Finally, at a time when almost every pathogen is becoming increasingly resistant to antimicrobials, we show that there is no evidence of circulating genomic resistance in C. trachomatis

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Foodborne infection of mice with Salmonella Typhimurium.

The bacterial pathogen Salmonella enterica serovar Typhimurium is one of the most common causes of foodborne disease in humans and is also an important model system for bacterial pathogenesis. Oral inoculation of C57Bl/6 mice, which are genetically susceptible to Salmonella, results in systemic infection but the murine intestine is not efficiently colonized unless the intestinal microbiota is disrupted. Pretreatment of C57Bl/6 mice with streptomycin, followed by oral inoculation with Salmonella Typhimurium results in colitis resembling human intestinal Salmonellosis. The predominant method of delivery of bacteria is oral gavage, during which organisms are deposited directly into the stomach via a feeding needle. Although convenient, this method can be stressful for mice, and may lead to unwanted tracheal or systemic introduction of bacteria. Here, we developed a method for oral infection of mice by voluntary consumption of regular mouse chow inoculated with bacteria. Mice readily ate chow fragments containing up to 108 CFU Salmonella, allowing for a wide range of infectious doses. In mice pretreated with streptomycin, infection with inoculated chow resulted in reproducible infections with doses as low as 103 CFU. Mice not treated with streptomycin, as well as resistant Nramp1 reconstituted C57Bl/6J mice, were also readily infected using this method. In summary, voluntary consumption of chow inoculated with Salmonella represents a natural route of infection for foodborne salmonellosis and a viable alternative to oral gavage

Edumarket: Manual de Marketing para a Educação Contínua

assistido ao aparecimento de milhões de empresas de formação, o que resultou numa intensificação da concorrência. Um grande número de instituições de ensino reconhece a importância do marketing em diversas áreas: identificação das necessidades dos futuros alunos, introdução de programas flexíveis de forma a ir ao encontro dessas necessidades, criação de uma boa imagem das instituições e aplicação de métodos de comunicação utilizados no marketing de forma atrair potenciais alunos. Todavia, os peritos europeus pertencentes a instituições que disponibilizam Educação Contínua não possuem ferramentas práticas que os ajudem a fazer uma avaliação precisa das necessidades individuais de potenciais participantes nas suas acções. Estes factores tornam a avaliação das estratégias de marketing e o desenvolvimento de uma ferramenta prática (Manual de Marketing) temas particularmente actuais para as instituições envolvidas da Educação Contínua. O Programa conhecido como "Aplicação dos Métodos e Ferramentas de Marketing na Educação Contínua" foi implementado por quatro países Europeus no âmbito dum projecto do programa SOCRATES - GRUNDTVIG. Parceiros do projecto * SZÁMALK Education Ltd. (HU) * University of Stratchclyde (UK) * Universidade do Porto (PT) * International Management Education (FI)assistido ao aparecimento de milhões de empresas de formação, o que resultou numa intensificação da concorrência. Um grande número de instituições de ensino reconhece a importância do marketing em diversas áreas: identificação das necessidades dos futuros alunos, introdução de programas flexíveis de forma a ir ao encontro dessas necessidades, criação de uma boa imagem das instituições e aplicação de métodos de comunicação utilizados no marketing de forma atrair potenciais alunos. Todavia, os peritos europeus pertencentes a instituições que disponibilizam Educação Contínua não possuem ferramentas práticas que os ajudem a fazer uma avaliação precisa das necessidades individuais de potenciais participantes nas suas acções. Estes factores tornam a avaliação das estratégias de marketing e o desenvolvimento de uma ferramenta prática (Manual de Marketing) temas particularmente actuais para as instituições envolvidas da Educação Contínua. O Programa conhecido como "Aplicação dos Métodos e Ferramentas de Marketing na Educação Contínua" foi implementado por quatro países Europeus no âmbito dum projecto do programa SOCRATES - GRUNDTVIG. Parceiros do projecto * SZÁMALK Education Ltd. (HU) * University of Stratchclyde (UK) * Universidade do Porto (PT) * International Management Education (FI