Excited States of Proton-bound DNA/RNA Base Homo-dimers: Pyrimidines

We are presenting the electronic photo fragment spectra of the protonated pyrimidine DNA bases homo-dimers. Only the thymine dimer exhibits a well structured vibrational progression, while protonated monomer shows broad vibrational bands. This shows that proton bonding can block some non radiative processes present in the monomer.Comment: We acknowledge the use of the computing facility cluster GMPCS of the LUMAT federation (FR LUMAT 2764

Efficacy and Safety Analyses of Recombinant Factor VIIa in Severe Post-Partum Hemorrhage

Background: Despite a range of available treatments, it is still sometimes challenging to treat patients with severe post-partum hemorrhage (sPPH). Objective: This study evaluated the efficacy and safety of recombinant activated factor VIIa (rFVIIa) in sPPH management. Methods: An open-label, multi-center, randomized controlled trial (RCT; NCT00370877) and four observational studies (OS; OS-1 (NCT04723979), OS-2, OS-3, and OS-4) were analyzed regarding efficacy (need for subsequent invasive procedures, including uterine compression sutures, uterine or iliac artery ligations, arterial embolization, or hysterectomy) and safety (incidence of thromboembolic events (TE) and maternal mortality) of rFVIIa for sPPH. The RCT, and OS-1 and OS-2, included a control group of women who did not receive rFVIIa (with propensity score-matching used in OS-1 and OS-2), whereas OS-3 and OS-4 provided descriptive data for rFVIIa-exposed women only. Results: A total of 446 women exposed to rFVIIa and 1717 non-exposed controls were included. In the RCT, fewer rFVIIa-exposed women (50% [21/42]) had an invasive procedure versus non-exposed women (91% [38/42]; odds ratio: 0.11; 95% confidence interval: 0.03–0.35). In OS-1, more rFVIIa-exposed women (58% [22/38]) had an invasive procedure versus non-exposed women (35% [13.3/38]; odds ratio: 2.46; 95% confidence interval: 1.06–5.99). In OS-2, 17% (3/18) of rFVIIa-exposed women and 32% (5.6/17.8) of non-exposed women had an invasive procedure (odds ratio: 0.33; 95% confidence interval: 0.03–1.75). Across all included women, TEs occurred in 1.5% (0.2% arterial and 1.2% venous) of rFVIIa-exposed women and 1.6% (0.2% arterial and 1.4% venous) of non-exposed women with available data. Conclusions: The positive treatment effect of rFVIIa on the RCT was not confirmed in the OS. However, the safety analysis did not show any increased incidence of TEs with rFVIIa treatment

A value-based comparison of the management of ambulatory respiratory diseases in walk-in clinics, primary care practices, and emergency departments : protocol for a multicenter prospective cohort study

Background: In Canada, 30%-60% of patients presenting to emergency departments are ambulatory. This category has been labeled as a source of emergency department overuse. Acting on the presumption that primary care practices and walk-in clinics offer equivalent care at a lower cost, governments have invested massively in improving access to these alternative settings in the hope that patients would present there instead when possible, thereby reducing the load on emergency departments. Data in support of this approach remain scarce and equivocal. Objective: The aim of this study is to compare the value of care received in emergency departments, walk-in clinics, and primary care practices by ambulatory patients with upper respiratory tract infection, sinusitis, otitis media, tonsillitis, pharyngitis, bronchitis, influenza-like illness, pneumonia, acute asthma, or acute exacerbation of chronic obstructive pulmonary disease. Methods: A multicenter prospective cohort study will be performed in Ontario and Québec. In phase 1, a time-driven activity-based costing method will be applied at each of the 15 study sites. This method uses time as a cost driver to allocate direct costs (eg, medication), consumable expenditures (eg, needles), overhead costs (eg, building maintenance), and physician charges to patient care. Thus, the cost of a care episode will be proportional to the time spent receiving the care. At the end of this phase, a list of care process costs will be generated and used to calculate the cost of each consultation during phase 2, in which a prospective cohort of patients will be monitored to compare the care received in each setting. Patients aged 18 years and older, ambulatory throughout the care episode, and discharged to home with one of the aforementioned targeted diagnoses will be considered. The estimated sample size is 1485 patients. The 3 types of care settings will be compared on the basis of primary outcomes in terms of the proportion of return visits to any site 3 and 7 days after the initial visit and the mean cost of care. The secondary outcomes measured will include scores on patient-reported outcome and experience measures and mean costs borne wholly by patients. We will use multilevel generalized linear models to compare the care settings and an overlap weights approach to adjust for confounding factors related to age, sex, gender, ethnicity, comorbidities, registration with a family physician, socioeconomic status, and severity of illness. Results: Phase 1 will begin in 2021 and phase 2, in 2023. The results will be available in 2025. Conclusions: The end point of our program will be for deciders, patients, and care providers to be able to determine the most appropriate care setting for the management of ambulatory emergency respiratory conditions, based on the quality and cost of care associated with each alternative

Identification of Keratinocyte Growth Factor as a Target of microRNA-155 in Lung Fibroblasts: Implication in Epithelial-Mesenchymal Interactions

International audienceBACKGROUND: Epithelial-mesenchymal interactions are critical in regulating many aspects of vertebrate embryo development, and for the maintenance of homeostatic equilibrium in adult tissues. The interactions between epithelium and mesenchyme are believed to be mediated by paracrine signals such as cytokines and extracellular matrix components secreted from fibroblasts that affect adjacent epithelia. In this study, we sought to identify the repertoire of microRNAs (miRNAs) in normal lung human fibroblasts and their potential regulation by the cytokines TNF-alpha, IL-1beta and TGF-beta. METHODOLOGY/PRINCIPAL FINDINGS: MiR-155 was significantly induced by inflammatory cytokines TNF-alpha and IL-1beta while it was down-regulated by TGF-beta. Ectopic expression of miR-155 in human fibroblasts induced modulation of a large set of genes related to "cell to cell signalling", "cell morphology" and "cellular movement". This was consistent with an induction of caspase-3 activity and with an increase in cell migration in fibroblasts tranfected with miR-155. Using different miRNA bioinformatic target prediction tools, we found a specific enrichment for miR-155 predicted targets among the population of down-regulated transcripts. Among fibroblast-selective targets, one interesting hit was keratinocyte growth factor (KGF, FGF-7), a member of the fibroblast growth factor (FGF) family, which owns two potential binding sites for miR-155 in its 3'-UTR. Luciferase assays experimentally validated that miR-155 can efficiently target KGF 3'-UTR. Site-directed mutagenesis revealed that only one out of the 2 potential sites was truly functional. Functional in vitro assays experimentally validated that miR-155 can efficiently target KGF 3'-UTR. Furthermore, in vivo experiments using a mouse model of lung fibrosis showed that miR-155 expression level was correlated with the degree of lung fibrosis. CONCLUSIONS/SIGNIFICANCE: Our results strongly suggest a physiological function of miR-155 in lung fibroblasts. Altogether, this study implicates this miRNA in the regulation by mesenchymal cells of surrounding lung epithelium, making it a potential key player during tissue injury

Effect of drought on grasslands: Soil core reciprocal transplantation experiment

Grassland ecosystems are challenged to meet the growing demand for ecosystem services and providing human goods. The expected increase in extreme climatic events will cause significant constraints on grassland systems that are particularly sensitive to drought. Identifying potential interactive effects of different factors, such as altitude and management, with different water availability scenarios is therefore a major challenge to anticipate the performance of grasslands and the reliability of production at a regional scale under future climate variability. The current project is part of the study of the response of pastures to simulated spring and summer droughts along an altitudinal gradient and according to two management schemes. It focuses on disentangling the soil effect from the drought treatment effect with a reciprocal transplantation experiment

Etude des variations du transcriptome après exposition aux rayons gamma chez Saccharomyces cerevisiae

L'exposition de la cellule à des rayonnements entraîne une réponse cellulaire dite radio- induite. D'une manière générale, celle-ci se traduit immédiatement par un arrêt (transitoire ou non) de la division cellulaire et par la réparation des lésions. Mon travail de thèse a consisté à étudier la réponse transcriptionnelle radio-induite à l'échelle génomique chez la levure S. cerevisiae. En utilisant la technologie des puces à ADN, nous avons comparé le transcriptome de cellules irradiées aux rayons gamma et non irradiées. Une première analyse a porté sur l'état transcriptionnel de 126 gènes, après exposition d'une souche diploïde à deux doses résultant en une survie cellulaire très différente. Cette étude, réalisée à différents temps après irradiation, pendant la période d'arrêt du cycle cellulaire, a mis en évidence un groupe de gènes potentiellement co-régulés. L'analyse globale du transcriptome après exposition aux rayons gamma a été réalisée en comparant la réponse transcriptionnelle radio-induite dans les trois types cellulaires de S. cerevisiae: la souche diploïde Mata/Mata et les souches haploïdes Mata et Mata. La dose à laquelle ont été exposées les cellules conduit à une différence de radiosensibilité selon la ploïdie des cellules. Un des résultats clé de cette analyse est la mise en évidence de l'induction spécifique de l'expression des gènes sub-télomériques dans les souches haploïdes. Une approche différente, rentrant dans la thématique de la réponse biologique aux faibles doses d'irradiation, a consisté à irradier les cellules durant 12 générations à des doses où aucune létalité ni retard de croissance ou modifications du matériel génétique n'étaient observés. Cette étude, assistée de plusieurs méthodes statistiques, montre l'existence d'un groupe de gènes, dont l'expression varie après une telle exposition et dont les produits sont localisés préférentiellement aux mitochondries.Exposure of cells to ionising radiation leads to the so-called radio-induced cellular response. In general, this response consisted in a cell cycle arrest and in the repair of the induced lesions. My PhD work consisted of a study of genome-wide radio-induced transcriptional response in the budding yeast Saccharomyces cerevisiae. Using DNA microarray technology, we compared genome-wide transcription levels in gamma-irradiated and unirradiated cells. The first sub-genomic analysis was carried out on 126 genes, after irradiation of diploid cells at two different doses that led to very different survival rates. The transcription level of the 126 genes was studied at different time points following irradiation and throughout the entire period of cell cycle arrest. It revealed that a group of genes are potentially co-regulated during the radio-induced cellular response. The transcriptional genome-wide analysis following gamma irradiation was carried out on three different S. cerevisiae cell types: the Mata/Mata diploid strain and the two Mata and Mata haploid strains. Exposure of these strains to the same level of ionising radiation led to very different rates of survival level. A major result of the analysis of these experiments was the demonstration that a specific set of sub-telomeric genes is specifically radio-induced in haploid strains. Using a different approach, we measured biological response to low levels of irradiation. Cells were irradiated during 12 generations at doses that neither led to any detectable lethality nor modifications of the genetic material. This study, which employed several statistical method, showed irradiation-induced changes at the transcription level for a group of genes whose products are preferentially located in the mitochondrion.ORSAY-PARIS 11-BU Sciences (914712101) / SudocSudocFranceF

Y-Chromosome DNA Haplotype XI in Eastern Europe

Haplotype XI frequencies at the Y-chromosome-specific DNA polymorphism (p49-TaqI) were reported in 639 males originating from 13 different geographic locations in Eastern Europe, where haplotype XI represents the major haplotype. The highest frequencies were obtained from Ukraine (44%), Russia (43.9%), and Hungary (40.7%). Percentages of haplotype XI geographic distribution show a gradient of decreasing frequency from these areas of higher percentages toward southeastern and more western countries in Europe

North African Genes in Iberia Studied by Y-Chromosome DNA Haplotype 5

The frequency of haplotype 5 at the Y-chromosome-specific DNA polymorphism (p49/TaqI) was reported in a study of 487 males originating from five different geographic locations in Iberia and North Africa. The highest frequency of haplotype 5 (68.9%) was previously observed in Berbers from Morocco, and it has been established that this haplotype is a characteristic Berber haplotype in North Africa. The relative frequencies of haplotype 5 distribution show a geographical gradient of decreasing frequency according to latitude in Iberia: 40.8% in Andalusia, 36.2% in Portugal, 12.1% in Catalonia, and 11.3% in the Basque Country; such a cline of decreasing frequency of haplotype 5 from the south to the north in Iberia clearly establishes a gene flow from North Africa towards Iberia

Population Distribution of the Methionine Allele at the PRNP Codon 129 Polymorphism in Europe and the Middle East

Methionine homozygosity at codon 129 of the prion protein gene is a risk factor for Creutzfeldt-Jakob disease. Knowledge of M129V polymorphism in normal populations may contribute to a better understanding of prion diseases. M129V polymorphism was studied in 2,201 normal subjects, originating from 15 populations from Europe and the Middle East. Mean heterozygosity in these populations is 38.9%, and there is some significant geographic heterogeneity between them. A comparison of M129 allele frequencies in these 15 populations to those already published for 8 European countries plus Turkey shows significant correlations with both latitude (r = −0.77) and longitude (r = 0.69). The geographic map of methionine allele frequencies indicates an east-west gradient of decreasing methionine allele values from the Middle East to Western Europe