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Rapid analysis of surrendered or seized drug samples provides important intelligence for health (e.g. treatment or harm reduction), and custodial services. Herein, three in-situ techniques, GC-MS, 1H NMR and FT-IR spectroscopy, with searchable libraries, are used to analyse 318 samples qualitatively, using technique specific library-based searches, obtained over the period 24th – 29th August 2019. 259 samples were identified as consisting of a single component, of which cocaine was the most prevalent (n = 158). Median match scores for all three techniques were ≥ 0.84 and showed agreement except for metformin (n = 1), oxandrolone (identified as vitamin K by IR (n = 4)), diazepam (identified as zolpidem by FT-IR (n = 2)) and 2-Br-4,5-DMPEA (n = 1), a structural isomer of 2C-B identified as a polymer of cellulose (cardboard) by FT-IR. 51 samples were found to consist of two or more components, of which 49 were adulterated cocaine samples (45 binary and 4 tertiary samples). GC-MS identified all components present in the 49 adulterated cocaine samples, whereas IR identified only cocaine in 88 % of cases (adulterant only = 12 %). The breakdown for 1H NMR spectroscopy was all components identified (51 %), cocaine only (33 %), adulterant only (10 %), cocaine and one adulterant (tertiary mixtures only, 6 %).

This study describes the first reported development of a rapid, generic gradient Ultra-High Performance Liquid Chromatography (UHPLC) methodology with targeted triple quadrupole MS/MS using electrospray positive ionisation to detect and unambiguously confirm the identity of 33 substituted 1, 2-diarylethamine (or diphenidine) derivatives in solid drug samples. The in-house synthesised library included a range of derivatives possessing either electron donating/withdrawing substituents, commonly included in combinatorial libraries, of varying size and lipophilicity on the phenyl ring. These test probes were used to investigate if their order of elution and that of their regioisomers were dependent on the position and type of the substituent on the phenyl ring. In addition, investigations into the retention mechanism of the diphenidines under reverse-phase UHPLC conditions were undertaken. Common adulterants found within seized bulk samples were assessed to prove that the methodology was specific, and the developed UHPLC-MS/MS (t G = 10 min) protocol was applied to confirm the identity of the psychoactive components within four seized bulk samples provided by law enforcement.

Early warning systems detect new psychoactive substances (NPS), while dedicated monitoring programs and routine drug and toxicology testing identify fluctuations in prevalence. We report the increasing prevalence of the synthetic cannabinoid receptor agonist (SCRA) ADB-BUTINACA (N-[1-amino-3,3-dimethyl-1-oxobutan-2-yl]-1-butyl-1H-indazole-3-carbox-amide). ADB-BUTINACA was first detected in a seizure in Sweden in 2019, and we report its detection in 13 routine Swedish forensic toxicology cases soon after. In January 2021, ADB-BUTINACA was detected in SCRA-infused papers seized in Scottish prisons and has rapidly increased in prevalence, being detected in 60.4% of the SCRA-infused papers tested between January and July 2021. In this work, ADB-BUTINACA was incubated with human hepatocytes (HHeps), and 21 metabolites were identified in vitro, 14 being detected in authentic case samples. The parent drug and metabolites B9 (mono-hydroxylation on the n-butyl tail) and B16 (mono-hydroxylation on the indazole ring) are recommended biomarkers in blood, while metabolites B4 (dihydrodiol formation on the indazole core), B9, and B16 are suitable biomarkers in urine. ADB-4en-PINACA (N-[1-amino-3,3-dimethyl-1-oxobutan-2-yl]-1-[pent-4-en-1-yl]-1H-indazole-3-carboxamide) was detected in Scottish prisons in December 2020, but, unlike ADB-BUTINACA, prevalence has remained low. ADB-4en-PINACA was incubated with HHeps, and 11 metabolites were identified. Metabolites E3 (dihydrodiol formed in the tail moiety) and E7 (hydroxylation on the linked/head group) are the most abundant metabolites in vitro and are suggested as urinary biomarkers. The in vitro potencies of ADB-BUTINACA (EC50, 11.5 nM and ADB-4en-PINACA (EC50, 11.6 nM) are similar to that of MDMB-4en-PINACA (EC50, 4.3 nM). A third tert-leucinamide SCRA, ADB-HEXINACA was also detected in prison samples and warrants further investigation. Funding Agencies|Linkopings Universitet; Dubai Police Force [2427681]; Leverhulme TrustLeverhulme Trust [RC-2015-01]; Scottish Prison Service [01865]; Linkoping University; VINNOVAVinnova [2019-03566]; European CommissionEuropean CommissionEuropean Commission Joint Research Centre [E! 113377]

Fentanyl, also known as ‘jackpot’, is a synthetic opiate that is 50–100 times more potent than morphine. Clandestine laboratories produce analogues of fentanyl, known as fentalogues to circumvent legislation regarding its production. Three pyridyl fentalogues were synthesized and then hyperpolarized by signal amplification by reversible exchange (SABRE) to appraise the forensic potential of the technique. A maximum enhancement of ‐168‐fold at 1.4 T was recorded for the ortho pyridyl 1H nuclei. Studies of the activation parameters for the three fentalogues revealed that the ratio of ligand loss trans to hydride and hydride loss in the complex [Ir(IMes)(L)3(H)2]+ (IMes=1,3‐bis(2,4,6‐trimethylphenyl)imidazole‐2‐ylidene) ranged from 0.52 to 1.83. The fentalogue possessing the ratio closest to unity produced the largest enhancement subsequent to performing SABRE at earth's magnetic field. It was possible to hyperpolarize a pyridyl fentalogue selectively from a matrix that consisted largely of heroin (97 : 3 heroin:fentalogue) to validate the use of SABRE as a forensic tool., No more hiding for pyridyl fentalogues! The hyperpolarization technique SABRE (signal amplification by reversible exchange) is utilised for the successful enhancement of 1H NMR signals of pyridyl functionalised fentalogues. We further demonstrate the successful selective polarization of one the fentalogues against a strong background‐signal of heroin.

Two-pore domain K

Background The development of RNA sequencing (RNAseq) and the corresponding emergence of public datasets have created new avenues of transcriptional marker search. The long non-coding RNAs (lncRNAs) constitute an emerging class of transcripts with a potential for high tissue specificity and function. Therefore, we tested the biomarker potential of lncRNAs on Mesenchymal Stem Cells (MSCs), a complex type of adult multipotent stem cells of diverse tissue origins, that is frequently used in clinics but which is lacking extensive characterization. Results We developed a dedicated bioinformatics pipeline for the purpose of building a cell-specific catalogue of unannotated lncRNAs. The pipeline performs ab initio transcript identification, pseudoalignment and uses new methodologies such as a specific k-mer approach for naive quantification of expression in numerous RNAseq data. We next applied it on MSCs, and our pipeline was able to highlight novel lncRNAs with high cell specificity. Furthermore, with original and efficient approaches for functional prediction, we demonstrated that each candidate represents one specific state of MSCs biology. Conclusions We showed that our approach can be employed to harness lncRNAs as cell markers. More specifically, our results suggest different candidates as potential actors in MSCs biology and propose promising directions for future experimental investigations.

The huge body of publicly available RNA-sequencing (RNA-seq) libraries is a treasure of functional information allowing to quantify the expression of known or novel transcripts in tissues. However, transcript quantification commonly relies on alignment methods requiring a lot of computational resources and processing time, which does not scale easily to large datasets. K-mer decomposition constitutes a new way to process RNA-seq data for the identification of transcriptional signatures, as k-mers can be used to quantify accurately gene expression in a less resource-consuming way. We present the Kmerator Suite, a set of three tools designed to extract specific k-mer signatures, quantify these k-mers into RNA-seq datasets and quickly visualize large dataset characteristics. The core tool, Kmerator, produces specific k-mers for 97% of human genes, enabling the measure of gene expression with high accuracy in simulated datasets. KmerExploR, a direct application of Kmerator, uses a set of predictor gene-specific k-mers to infer metadata including library protocol, sample features or contaminations from RNA-seq datasets. KmerExploR results are visualized through a user-friendly interface. Moreover, we demonstrate that the Kmerator Suite can be used for advanced queries targeting known or new biomarkers such as mutations, gene fusions or long non-coding RNAs for human health applications.

[Image: see text] An automated approach to the collection of (1)H NMR (nuclear magnetic resonance) spectra using a benchtop NMR spectrometer and the subsequent analysis, processing, and elucidation of components present in seized drug samples are reported. An algorithm is developed to compare spectral data to a reference library of over 300 (1)H NMR spectra, ranking matches by a correlation-based score. A threshold for identification was set at 0.838, below which identification of the component present was deemed unreliable. Using this system, 432 samples were surveyed and validated against contemporaneously acquired GC–MS (gas chromatography–mass spectrometry) data. Following removal of samples which possessed no peaks in the GC–MS trace or in both the (1)H NMR spectrum and GC–MS trace, the remaining 416 samples matched in 93% of cases. Thirteen of these samples were binary mixtures. A partial match (one component not identified) was obtained for 6% of samples surveyed whilst only 1% of samples did not match at all.

Over recent years there has been a progressive increase in the adulteration of common illicit street drugs, such as heroin and cocaine, with fentanyl and its derivatives (fentalogues) being the cause of over doses ending with fatal repercussions. Consequently, there is a need for the development of sensitive, selective and reliable analytical protocols for their separation and quantification. Herein, we report for the first time, a combination of high-performance liquid chromatography with a dual-diode array and electrochemical (amperometric) detector achieved for the simultaneous detection and quantification of heroin (HRN), fentanyl and ten fentalogues; the amperometric detection is achieved using a commercially available impinging jet flow-cell that incorporates in-house screen-printed graphite macroelectrodes (SPEs). Both protocols are analytically compared and contrasted in terms of their experimental parameters and chromatographic conditions with the separation and quantification being optimized, with these protocols demonstrating a high sensitivity and reproducibility. The proposed methods were successfully applied for the analysis of the investigated drugs of abuse, in the presence of common adulterants (e.g. caffeine, paracetamol and benzocaine), co-formulated excipients (starch, lactose, aerosil 200, etc.) and simultaneously within seized street samples.

Supercritical Fluid Chromatography (SFC-UV) employing a carbon dioxide (CO 2) and 10 mM ammonium acetate in MeOH-water (95:5 v/v) gradient provides a rapid analysis (t G

Fluorinated fentanyl regioisomers have become increasingly common in forensic casework. This study reports the synthesis of eight fluorinated fentanyl derivatives as pure reference materials and their complete NMR, infrared and mass spectral characterisation. Presumptive colour tests and TLC results are presented as an initial screening method for these compounds. The fully validated GC–MS method (employing SIM mode) allows the quantification of the target analytes (LOD = 9 – 20 ng/mL, LOQ = 31 – 67 ng/mL), fentanyl, heroin, acetaminophen and caffeine, within 13 minutes. In most cases, the regioisomeric fluorofentanyls were resolved from each other except for the 3’- and 4’-fluorinated derivatives (5b and 5c). To achieve full separation, an orthogonal benchtop 19F NMR method allows the identification and quantification of target analogues (LOD = 74 – 400 μg/mL, LOQ = 290 – 1340 μg/mL). The 19F NMR method allows the detection of fluorinated fentanyl analogues at a low concentration (2.4% w/w) in heroin.

The huge body of publicly available RNA-sequencing (RNA-seq) libraries is a treasure of functional information allowing to quantify the expression of known or novel transcripts in tissues. However, transcript quantification commonly relies on alignment methods requiring a lot of computational resources and processing time, which does not scale easily to large datasets. K-mer decomposition constitutes a new way to process RNA-seq data for the identification of transcriptional signatures, as k-mers can be used to quantify accurately gene expression in a less resource-consuming way. We present the Kmerator Suite, a set of three tools designed to extract specific k-mer signatures, quantify these k-mers into RNA-seq datasets and quickly visualize large dataset characteristics. The core tool, Kmerator, produces specific k-mers for 97% of human genes, enabling the measure of gene expression with high accuracy in simulated datasets. KmerExploR, a direct application of Kmerator, uses a set of predictor gene-specific k-mers to infer metadata including library protocol, sample features or contaminations from RNA-seq datasets. KmerExploR results are visualized through a user-friendly interface. Moreover, we demonstrate that the Kmerator Suite can be used for advanced queries targeting known or new biomarkers such as mutations, gene fusions or long non-coding RNAs for human health applications.

Recreational MDMA use is a worldwide problem. Tablet dosage varies, thus entailing a requirement for quantitative analysis. The quantification of MDMA in tablets using benchtop 1H NMR spectroscopy via either linear regression (‘manual’ method) or partial least square regression (‘automated’ method) approaches are reported, without the need for an internal standard, and compared against contemporaneously obtained GC–MS data. Twenty samples were evaluated of which 15 were proven to contain MDMA, via qualitative NMR (hit score ≥ 0.97) and GC–MS (Rt = 5.6 min) analysis. Quantitative NMR analysis showed that the mean value of MDMA content was 42.6% w/w by the manual method and 45.9% w/w by the automated method. The mean value obtained from GC analysis was 44.0% w/w. A substantial proportion (n = 9) of the tablets tested possessed > 190 mg of MDMA (range 133–223 mg, average of all techniques’ calculations for each tablet). This value is higher than the reported average MDMA content of tablets by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA), which was ca. 125 mg of MDMA per tablet in 2016.

The development of RNA sequencing (RNAseq) and corresponding emergence of public datasets have created new avenues of transcriptional marker search. The long non-coding RNAs (lncRNAs) constitute an emerging class of transcripts with a potential for high tissue specificity and function. Using a dedicated bioinformatics pipeline, we propose to construct a cell-specific catalogue of unannotated lncRNAs and to identify the strongest cell markers. This pipeline uses ab initio transcript identification, pseudoalignment and new methodologies such as a specific k-mer approach for naive quantification of expression in numerous RNAseq data.For an application model, we focused on Mesenchymal Stem Cells (MSCs), a type of adult multipotent stem-cells of diverse tissue origins. Frequently used in clinics, these cells lack extensive characterisation. Our pipeline was able to highlight different lncRNAs with high specificity for MSCs. In silico methodologies for functional prediction demonstrated that each candidate represents one specific state of MSCs biology. Together, these results suggest an approach that can be employed to harness lncRNA as cell marker, showing different candidates as potential actors in MSCs biology, while suggesting promising directions for future experimental investigations.

Il y a presque deux cents ans apparaissait en Bretagne un nouveau modèle scolaire, l'enseignement mutuel. Né en Angleterre dans le sillage de la révolution industrielle, du besoin à la fois de protéger les enfants du vagabondage et du désir de leur donner une première instruction, il séduit les philanthropes et les libéraux français qui veulent régénérer mais aussi contrôler le peuple. L'enseignement mutuel s'apparente alors, à l'instar de la vaccine ou de la pomme de terre, aux bienfaits promis aux pauvres que ce début de siècle annonce. Cette instruction se veut économique. On cherchera alors à rassembler un maximum d'élèves dans un même lieu, jusqu'à plusieurs centaines. À la tête de cette école nombreuse, un seul maître sera nécessaire, des moniteurs pris parmi les enfants y seront les véritables instructeurs. Le matériel sera peu onéreux. Des ardoises, des crayons et des tableaux suffiront. Cette instruction se veut également rapide et efficace. On établira donc un programme d'enseignement précis pour chacune des huit classes de lecture, d'écriture et d'arithmétique, celles-ci étant organisées selon une gradation progressive de la difficulté. Les techniques seront celles de l'imprégnation et de la mémorisation. Pour susciter l'émulation parmi les élèves, ceux-ci seront rangés, sur leurs bancs, en fonction de leurs succès. Ils récolteront par ailleurs bons points, médailles et récompenses diverses. Le système est bien pensé et a de quoi séduire mais comment est-il accueilli par la population bretonne qui a peu éprouvé le besoin de s'instruire jusque-là ? Plus particulièrement, quel est le rôle des élites dans cette entreprise ? Quel est celui du clergé dont on connaît l'influence prépondérante, surtout en ce qui concerne la formation des esprits ? En outre, comment les maîtres choisis pour les nouvelles écoles vont-ils vivre cette aventure inédite ? En sortiront-ils grandis professionnellement et socialement ? Enfin, quelle est l'efficacité réelle de la nouvelle méthode ?

Élaboré à partir d’une belle thèse de doctorat, soutenue devant l’université de Rennes 2, en juin 2008, ce livre évoque un aspect peu connu de l’enseignement primaire du XIXe siècle, celui des écoles mutuelles. Introduit à Paris au début de la Restauration, l’enseignement mutuel, à vocation urbaine, connaît deux phases de succès, avant de faire l’objet de polémiques, voire de dures critiques sous la monarchie de Juillet, puis de disparaître définitivement sous le Second Empire. L’originalité ...

International audience; L1 retrotransposons are transposable elements and major contributors of genetic variation in humans. Where L1 integrates into the genome can directly impact human evolution and disease. Here, we experimentally induced L1 retrotransposition in cells and mapped integration sites at nucleotide resolution. At local scales, L1 integration is mostly restricted by genome sequence biases and the specificity of the L1 machinery. At regional scales, L1 shows a broad capacity for integration into all chromatin states, in contrast to other known mobile genetic elements. However, integration is influenced by the replication timing of target regions, suggesting a link to host DNA replication. The distribution of new L1 integrations differs from those of preexisting L1 copies, which are significantly reshaped by natural selection. Our findings reveal that the L1 machinery has evolved to efficiently target all genomic regions and underline a predominant role for post-integrative processes on the distribution of endogenous L1 elements.

The Plasmodium falciparum var gene family encodes ∼60 surface antigens by which parasites escape the host immune responses via clonal expression of var genes. However, the mechanism controlling this mutual exclusivity, associated with alterations in chromatin assembly, is not understood. Here, we determined how expression of the var gene family is regulated by two RecQ DNA helicase family members, PfRecQ1 and PfWRN, in P. falciparum . Through genetic manipulation, we found that the complete var repertoire was silenced on PfRecQ1 knockout, whereas their expression did not show noticeable changes when PfWRN was knocked out. More important, mutually exclusive expression of var genes could be rescued by complementation of PfRecQ1. In addition, knocking out either of these two helicase genes changed the perinuclear cluster distribution of subtelomeres and subtelomeric var genes. Whereas deletion of PfRecQ1 increased the heterochromatin mark trimethylated (H3K9me3) at the transcription start site (TSS) of the var gene upsC1 , that deletion had no effect on the global distribution of H3K9me3 over gene bodies, including those for the var genes. ChIP-seq assay showed that PfRecQ1 was enriched globally at the TSSs of all genes, whereas PfWRN-enriched regions occurred at the gene bodies of the var gene family, but not of other genes or at TSSs of all genes. On PfRecQ1 deletion, the upsC1 var gene moved from the active perinuclear transcription region to a silenced region of the upsC type. These findings imply that PfRecQ1, but not PfWRN, is essential for maintaining the clonal expression of var genes.

The Plasmodium falciparum var gene family encodes ∼60 surface antigens by which parasites escape the host immune responses via clonal expression of var genes. However, the mechanism controlling this mutual exclusivity, associated with alterations in chromatin assembly, is not understood. Here, we determined how expression of the var gene family is regulated by two RecQ DNA helicase family members, PfRecQ1 and PfWRN, in P. falciparum. Through genetic manipulation, we found that the complete var repertoire was silenced on PfRecQ1 knockout, whereas their expression did not show noticeable changes when PfWRN was knocked out. More important, mutually exclusive expression of var genes could be rescued by complementation of PfRecQ1. In addition, knocking out either of these two helicase genes changed the perinuclear cluster distribution of subtelomeres and subtelomeric var genes. Whereas deletion of PfRecQ1 increased the heterochromatin mark trimethylated (H3K9me3) at the transcription start site (TSS) of the var gene upsC1, that deletion had no effect on the global distribution of H3K9me3 over gene bodies, including those for the var genes. ChIP-seq assay showed that PfRecQ1 was enriched globally at the TSSs of all genes, whereas PfWRN-enriched regions occurred at the gene bodies of the var gene family, but not of other genes or at TSSs of all genes. On PfRecQ1 deletion, the upsC1 var gene moved from the active perinuclear transcription region to a silenced region of the upsC type. These findings imply that PfRecQ1, but not PfWRN, is essential for maintaining the clonal expression of var genes.

Background: High-throughput next generation sequencing (NGS) technologies enable the detection of biomarkers used for tumor classification, disease monitoring and cancer therapy. Whole-transcriptome analysis using RNA-seq is important, not only as a means of understanding the mechanisms responsible for complex diseases but also to efficiently identify novel genes/exons, splice isoforms, RNA editing, allele-specific mutations, differential gene expression and fusion-transcripts or chimeric RNA (chRNA). Methods: We used Crac, a tool that uses genomic locations and local coverage to classify biological events and directly infer splice and chimeric junctions within a single read. Crac’s algorithm extracts transcriptional chimeric events irrespective of annotation with a high sensitivity, and CracTools was used to aggregate, annotate and filter the chRNA reads. The selected chRNA candidates were validated by real time PCR and sequencing. In order to check the tumor specific expression of chRNA, we analyzed a publicly available dataset using a new tag search approach. Results: We present data related to acute myeloid leukemia (AML) RNA-seq analysis. We highlight novel biological cases of chRNA, in addition to previously well characterized leukemia chRNA. We have identified and validated 17 chRNAs among 3 AML patients: 10 from an AML patient with a translocation between chromosomes 15 and 17 (AML-t(15;17), 4 from patient with normal karyotype (AML-NK) 3 from a patient with chromosomal 16 inversion (AML-inv16). The new fusion transcripts can be classified into four groups according to the exon organization. Conclusions: All groups suggest complex but distinct synthesis mechanisms involving either collinear exons of different genes, non-collinear exons, or exons of different chromosomes. Finally, we check tumor-specific expression in a larger RNA-seq AML cohort and identify new AML biomarkers that could improve diagnosis and prognosis of AML.

International audience; AbstractThe third international conference on Transposable Elements (ICTE) was held 16–19 April 2016 in Saint Malo, France. Organized by the French Transposition Community (Research group of the CNRS: “Mobile genetic elements: from mechanism to populations, an integrative approach”) and the French Society of Genetics, the conference’s goal was to bring together researchers who study transposition in diverse organisms, using multiple experimental approaches. The meeting gathered 180 participants from all around the world. Most of them contributed through poster presentations, invited talks and short talks selected from poster abstracts. The talks were organized into six scientific sessions: “Taming mobile DNA: self and non-self recognition”; “Trans-generational inheritance”; “Mobile DNA genome structure and organization, from molecular mechanisms to applications”; “Remembrance of (retro)transposon past: mobile DNA in genome evolution”; and finally “The yin and the yang of mobile DNA in human health”.

Trace emerging contaminants (ECs) occur in both waste and surface waters that are rich in particulates that have been found to sorb several organic contaminants. An analytical method based on off-line solid-phase extraction (SPE) followed by liquid chromatography-mass spectrometry (LC-MS) analysis was developed for the detection and quantification of 31 ECs from surface water, wastewater, suspended particulate matter (SPM) as well as sediments. Lyophilized sediments and air-dried SPM were subjected to ultrasonic extraction. Water samples and extracts were then concentrated and cleaned-up by off-line SPE. Quantification was realized using a Q Exactive mass spectrometer in both full scan (FS) and MS2 modes. These two modes were optimized and compared to determine which one was the most suitable for each matrix studied. Yeast estrogen screen assay (YES-assay) adapted from the direct measurement of estrogenic activity without sample extraction was tested on filtered wastewater samples. An endocrine disrupting effect was detected in all effluent samples analyzed with estradiol equivalent concentrations ranging from 4.4 to 720 ng eq E2 L−1 for the WWTP-1 and 6.5–42 ng eq E2 L−1 for the WWTP-2. The analytical methods were also applied on six samples of surface water, the corresponding SPM, the sediments and thirty-nine effluent samples from two wastewater treatment plants (WWTPs) sampled over a period of five months (February to June 2014).

Cet article présente une vue d’ensemble des outils et des méthodes de travail du compositeur José Evangelista. Après avoir discuté de la relation qu’entretient le compositeur avec le piano et l’ordinateur en tant qu’outils compositionnels, on examine le rôle des notes textuelles et des esquisses dans ses habitudes de travail. À l’aide d’exemples tirés des esquisses d’Alap et Gat (1998) et de Viola Song (2002), on découvre une méthode de travail où notes textuelles et esquisses musicales s’enchevêtrent et se fertilisent mutuellement. On constate également que le travail assidu du compositeur sur les procédés hétérophoniques a permis à sa méthode de travail de se développer de façon continue, sans grandes ruptures, au cours des 25 dernières années. On conclut de cet examen que, chez Evangelista, méthode de travail et esthétique constituent un tout organique à l’intérieur duquel la subjectivité du compositeur s’exprime sans entraves., This article presents an overview of the tools and working methods of composer José Evangelista. After discussing his relationship with the piano and the computer as compositional tools, we examine the role of textual notes and drafts in his working habits. On the basis of examples drawn from the drafts of Alap et Gat (1998) and Viola Song (2002), we discover a working method in which written text and musical drafts cohabitate and fertilize each other. We also note that the composer’s assiduous work on heterophonic processes allowed for a continuous evolution of his working method over the last 25 years. We conclude this examination by stating that in Evangelista’s work, working method and aesthetics constitute an organic whole within which the composer’s subjectivity expresses itself freely.

Michel Denis compte parmi les personnalités qui ont fortement marqué l’histoire universitaire de Rennes et de l’Ouest armoricain en général. C’est d’abord vrai pour son propre parcours biographique – de l’étudiant des années cinquante, à la faculté des lettres, au professeur à l’institut d’études politiques de Rennes –, c’est vrai aussi pour son apport scientifique : Michel Denis est l’incomparable historien du monde conservateur de l’Ouest, aristocratique et clérical. Approfondissant et dépassant singulièrement les intuitions d’André Siegfried, il est l’un des premiers à avoir mis en lumière le processus dialectique de modernisation contrôlée par des élites conservatrices, également observable en d’autres régions d’Europe. L’action de Michel Denis ne s’est pas arrêtée à l’enseignement et à la recherche. Héritier des Rennais de 1789, passionnés pour la cité et la liberté, dont il a retracé récemment l’histoire, il a marqué de son sceau la présidence de l’université Rennes 2 et déployé son énergie au service du développement des institutions régionales. Une vingtaine de collègues et amis rendent ici hommage à Michel Denis, à travers des textes organisés autour de ce qui constitue ses centres d’intérêt, voire de passion : l’Ouest intérieur, la Bretagne contemporaine, l’Université et la Cité.

Dès lors qu’il s’agit d’enseignement français, l’Allemagne demeure une référence pendant tout le xixe siècle. Le voyage de Victor Cousin outre-Rhin en 1831 avant le vote de la loi Guizot sur l’enseignement primaire, les ouvrages d’Eugène Rendu et de Saint-Marc Girardin, également sous la Monarchie de Juillet, la mission de l’inspecteur général Jean Magloire Baudoin pour l’étude de l’enseignement primaire et de l’enseignement spécial en Allemagne avant la création officielle, en 1865, de l’ens...

Cet ouvrage fait le point sur les connaissances relatives à l'habitat rural en pays d'habitat dispersé. L'objectif est de travailler sur un objet concret et fort répandu – la maison rurale – et de le traiter dans la très longue durée, de l'Antiquité à la période contemporaine, à la fois comme un objet d'histoire, d'archéologie et de patrimoine. La maison rurale est celle de l'agriculteur, mais elle est aussi celle du vigneron, de l'instituteur, du bourgeois qui en fait sa résidence secondaire. En région d'habitat dispersé, la maison n'est pas dissociable de son environnement, constitué des bâtiments d'exploitation mais aussi des espaces communs qui sont autant de lieux de sociabilité. Plusieurs études s'attachent ici à répondre à une question difficile : celle du confort offert par les maisons rurales aux différentes époques. La maison rurale antérieure à la modernisation de la seconde moitié du XIXe siècle n'est pas systématiquement la chaumière popularisée par les contes et les folkloristes ! Et dès le XVIIe siècle, certaines maisons rurales sont bâties de belles pierres de taille et comportent des escaliers intérieurs. L'espace géographique couvert par cet ouvrage est très vaste : l'ouest de la France (Normandie, Bretagne, Poitou, Touraine, Maine), l'Aquitaine et le Toulousain, la Limagne, le Cantal et les Cévennes, les Pyrénées orientales, la vallée de l'Adour, les Landes de Gascogne... mais aussi, hors du territoire national, la Galice et les Provinces du Québec ; toutes régions caractérisées aujourd'hui encore par un habitat dispersé. Au total, les études de ce livre portent donc sur des domaines tout à fait neufs de la recherche qui pourront nourrir la réflexion des aménageurs et les spécialistes du tourisme culturel. Ils trouveront dans ces travaux des appuis théoriques et pratiques qui leur permettront de poursuivre une politique de valorisation de ce patrimoine extrêmement riche.

Dans une brochure de 48 pages, publiée sous le Second Empire, quinze ans avant l'arrivée de Jules Ferry au ministère de l'Instruction publique, le maître des requêtes au Conseil d'État, Charles Frédéric Robert écrit : « Aucune statistique ne prendra mieux l'état vrai d'un grand nombre de maisons d'école que les descriptions qu'en ont faites les instituteurs eux-mêmes, parlant en pleine liberté et à cœur ouvert ». En effet, en décembre 1860, dans le cadre d'un concours ministériel, les institu...

Supplementary Material : Supplementary tables S1–S3andfigure S1areavailableatMolecular Biology and Evolutiononline (http://www.mbe.oxfordjournals.org/).; International audience; Transposable elements comprise more than 45% of the human genome and long interspersed nuclear element 1 (LINE-1 or L1) is the only autonomous mobile element remaining active. Since its identification, it has been proposed that L1 contributes to the mobilization and amplification of other cellular RNAs and more recently, experimental demonstrations of this function has been described for many transcripts such as Alu, a nonautonomous mobile element, cellular mRNAs, or small noncoding RNAs. Detailed examination of the mobilization of various cellular RNAs revealed distinct pathways by which they could be recruited during retrotransposition; template choice or template switching. Here, by analyzing genomic structures and retrotransposition signatures associated with small nuclear RNA (snRNA) sequences, we identified distinct recruiting steps during the L1 retrotransposition cycle for the formation of snRNA-processed pseudogenes. Interestingly, some of the identified recruiting steps take place in the nucleus. Moreover, after comparison to other vertebrate genomes, we established that snRNA amplification by template switching is common to many LINE families from several LINE clades. Finally, we suggest that U6 snRNA copies can serve as markers of L1 retrotransposition dynamics in mammalian genomes.

B1 elements are an abundant class of short interspersed elements (SINEs) in the mouse genome and mobilize by a process known as retrotransposition. Here, we report the characterization of a mutagenic B1 insertion into exon 4 of the Atcay gene, which was previously shown to be responsible for the jittery mouse. Mutations in the human ortholog of this gene, ATCAY, are responsible for Cayman ataxia. The B1 insertion is B150-bp long, ends in a 45–50-bp polyadenylic acid (poly A) tail, is flanked by a perfect 13-bp target-site duplication, and is inserted into a sequence that resembles a LINE-1 endonuclease consensus cleavage site. Computational analysis indicates that the mutagenic insertion is most closely related to elements of the B1-C subfamily, and we have identified two possible progenitor B1 sequences on mouse chromosome 19. Together, these data demonstrate that B1 retrotransposition is ongoing in the mouse genome and is consistent with the hypothesis that the reverse transcriptase and endonuclease encoded by LINE-1 elements mediate B1 mobility. Hum Mutat 24:9–13, 2004. r 2004 Wiley-Liss, Inc.

Long interspersed nuclear elements (LINEs or L1s) comprise approximately 17% of human DNA; however, only about 60 of the approximately 400,000 L1s are mobile. Using a retrotransposition assay in cultured human cells, we demonstrate that L1-encoded proteins predominantly mobilize the RNA that encodes them. At much lower levels, L1-encoded proteins can act in trans to promote retrotransposition of mutant L1s and other cellular mRNAs, creating processed pseudogenes. Mutant L1 RNAs are mobilized at 0.2 to 0.9% of the retrotransposition frequency of wild-type L1s, whereas cellular RNAs are mobilized at much lower frequencies (ca. 0.01 to 0.05% of wild-type levels). Thus, we conclude that L1-encoded proteins demonstrate a profound cis preference for their encoding RNA. This mechanism could enable L1 to remain retrotransposition competent in the presence of the overwhelming number of nonfunctional L1s present in human DNA.

Comme le rappelle Jean-François Condette dès l’introduction, ce livre, né d’une demande et du constat d’un manque, « n’est pas une thèse, mais une synthèse ». Divisé en cinq chapitres, de longueur inégale, habilement complétés par de nombreux documents (36 au total), l’ouvrage combine le respect de la chronologie avec des aspects plus thématiques, présentés sur une période longue (le modèle normalien de 1833 à 1940, la question de la formation professionnelle des enseignants du secondaire ent...

Background Plant leucine-rich repeat receptor-like kinases (LRR-RLKs) are receptor kinases that contain LRRs in their extracellular domain. In the last 15 years, many research groups have demonstrated major roles played by LRR-RLKs in plants during almost all developmental processes throughout the life of the plant and in defense/resistance against a large range of pathogens. Recently, a breakthrough has been made in this field that challenges the dogma of the specificity of plant LRR-RLKs. Results We analyzed ~1000 complete genomes and show that LRR-RK genes have now been identified in 8 non-plant genomes. We performed an exhaustive phylogenetic analysis of all of these receptors, revealing that all of the LRR-containing receptor subfamilies form lineage-specific clades. Our results suggest that the association of LRRs with RKs appeared independently at least four times in eukaryotic evolutionary history. Moreover, the molecular evolutionary history of the LRR-RKs found in oomycetes is reminiscent of the pattern observed in plants: expansion with amplification/deletion and evolution of the domain organization leading to the functional diversification of members of the gene family. Finally, the expression data suggest that oomycete LRR-RKs may play a role in several stages of the oomycete life cycle. Conclusions In view of the key roles that LRR-RLKs play throughout the entire lifetime of plants and plant-environment interactions, the emergence and expansion of this type of receptor in several phyla along the evolution of eukaryotes, and particularly in oomycete genomes, questions their intrinsic functions in mimicry and/or in the coevolution of receptors between hosts and pathogens.

Fruit d’un travail d’équipe, l’ouvrage de Marcel Grandière constitue une nouvelle synthèse de l’histoire de la formation des maîtres, de la Révolution française à la Première Guerre mondiale. Respectant une chronologie classique, il se compose de trois parties équilibrées. Dès l’introduction, le lecteur est fixé sur la vocation de ce travail qui privilégie l’histoire « par en haut », s’appuyant sur un corpus de plus de 220 textes officiels et sur toute une littérature pédagogique.Dans la prem...