The effects of physiologically plausible connectivity structure on local and global dynamics in large scale brain models.

Functionally relevant large scale brain dynamics operates within the framework imposed by anatomical connectivity and time delays due to finite transmission speeds. To gain insight on the reliability and comparability of large scale brain network simulations, we investigate the effects of variations in the anatomical connectivity. Two different sets of detailed global connectivity structures are explored, the first extracted from the CoCoMac database and rescaled to the spatial extent of the human brain, the second derived from white-matter tractography applied to diffusion spectrum imaging (DSI) for a human subject. We use the combination of graph theoretical measures of the connection matrices and numerical simulations to explicate the importance of both connectivity strength and delays in shaping dynamic behaviour. Our results demonstrate that the brain dynamics derived from the CoCoMac database are more complex and biologically more realistic than the one based on the DSI database. We propose that the reason for this difference is the absence of directed weights in the DSI connectivity matrix.

Large A-fiber activity is required for microglial proliferation and p38 MAPK activation in the spinal cord: different effects of resiniferatoxin and bupivacaine on spinal microglial changes after spared nerve injury.

BACKGROUND: After peripheral nerve injury, spontaneous ectopic activity arising from the peripheral axons plays an important role in inducing central sensitization and neuropathic pain. Recent evidence indicates that activation of spinal cord microglia also contributes to the development of neuropathic pain. In particular, activation of p38 mitogen-activated protein kinase (MAPK) in spinal microglia is required for the development of mechanical allodynia. However, activity-dependent activation of microglia after nerve injury has not been fully addressed. To determine whether spontaneous activity from C- or A-fibers is required for microglial activation, we used resiniferatoxin (RTX) to block the conduction of transient receptor potential vanilloid subtype 1 (TRPV1) positive fibers (mostly C- and Adelta-fibers) and bupivacaine microspheres to block all fibers of the sciatic nerve in rats before spared nerve injury (SNI), and observed spinal microglial changes 2 days later. RESULTS: SNI induced robust mechanical allodynia and p38 activation in spinal microglia. SNI also induced marked cell proliferation in the spinal cord, and all the proliferating cells (BrdU+) were microglia (Iba1+). Bupivacaine induced a complete sensory and motor blockade and also significantly inhibited p38 activation and microglial proliferation in the spinal cord. In contrast, and although it produced an efficient nociceptive block, RTX failed to inhibit p38 activation and microglial proliferation in the spinal cord. CONCLUSION: (1) Blocking peripheral input in TRPV1-positive fibers (presumably C-fibers) is not enough to prevent nerve injury-induced spinal microglial activation. (2) Peripheral input from large myelinated fibers is important for microglial activation. (3) Microglial activation is associated with mechanical allodynia.

Diffuse large B-cell lymphoma of Waldeyer's ring has distinct clinicopathologic features: a GELA study.

BACKGROUND: Diffuse large B-cell lymphomas (DLBCLs) arising in specific extranodal sites have peculiar clinicopathologic features. PATIENTS AND METHODS: We analyzed a cohort of 187 primary Waldeyer's ring (WR) DLBCLs retrieved from GELA protocols using anthracyclin-based polychemotherapy. RESULTS: Most patients (92%) had stage I-II disease. A germinal center B-cell-like (GCB) immunophenotype was observed in 61%, and BCL2 expression in 55%, of WR DLBCLs. BCL2, BCL6, IRF4 and MYC breakpoints were observed in, respectively, 3 of 42 (7%), 9 of 36 (25%), 2 of 26 (8%) and 4 of 40 (10%) contributive cases. A variable follicular pattern was evidenced in 30 of 68 (44%) large biopsy specimens. The 5-year progression-free survival (PFS) and the overall survival (OS) of 153 WR DLBCL patients with survival information were 69.5% and 77.8%, respectively. The GCB immunophenotype correlated with a better OS (P = 0.0015), while BCL2 expression predicted a worse OS (P = 0.037), an effect overcome by the GCB/non-GCB classification. Compared with matched nodal DLBCLs, WR DLBCLs with no age-adjusted international prognostic index factor disclosed a better 5-year PFS rate (77.5% versus 70.7%; P = 0.03). CONCLUSIONS: WR DLBCLs display distinct clinicopathologic features compared with conventional DLBCLs, with usual localized-stage disease, common follicular features and a high frequency of GCB immunophenotype contrasting with a low rate of BCL2 rearrangements. In addition, they seem to be associated with a better outcome than their nodal counterpart.

Large calcite and bulk-rock volume loss in metacarbonate xenoliths from the Qu,rigut massif (French Pyrenees)

Chemical mass transfer was quantified in a metacarbonate xenolith enclosed within the granodiorite of the Qu,rigut massif (Pyrenees, France). Mass balance calculations suggest a strong decrease of CaO, SrO and CO(2) contents (up to -90%), correlated with a decrease of modal calcite content as the contact is approached. Most other chemical elements behave immobile during metasomatism. They are therefore passively enriched. Only a small increase of SiO(2), Al(2)O(3) and Fe(2)O(3) contents occurs in the immediate vicinity of the contact. Hence, in this study, skarn formation is characterized by the lack of large chemical element influx from the granitoid protolith. A large decrease of the initial carbonate volume (up to -86%) resulted from a combination of decarbonation reactions and loss of CaO and CO(2). The resulting volume change has potentially important consequences for the interpretation of stable isotope profiles: the isotope alteration could have occured over greater distances than those observed today.

Like-acetylglucosaminyltransferase (LARGE)-dependent modification of dystroglycan at Thr-317/319 is required for laminin binding and arenavirus infection.

α-dystroglycan is a highly O-glycosylated extracellular matrix receptor that is required for anchoring of the basement membrane to the cell surface and for the entry of Old World arenaviruses into cells. Like-acetylglucosaminyltransferase (LARGE) is a key molecule that binds to the N-terminal domain of α-dystroglycan and attaches ligand-binding moieties to phosphorylated O-mannose on α-dystroglycan. Here we show that the LARGE modification required for laminin- and virus-binding occurs on specific Thr residues located at the extreme N terminus of the mucin-like domain of α-dystroglycan. Deletion and mutation analyses demonstrate that the ligand-binding activity of α-dystroglycan is conferred primarily by LARGE modification at Thr-317 and -319, within the highly conserved first 18 amino acids of the mucin-like domain. The importance of these paired residues in laminin-binding and clustering activity on myoblasts and in arenavirus cell entry is confirmed by mutational analysis with full-length dystroglycan. We further demonstrate that a sequence of five amino acids, Thr(317)ProThr(319)ProVal, contains phosphorylated O-glycosylation and, when modified by LARGE is sufficient for laminin-binding. Because the N-terminal region adjacent to the paired Thr residues is removed during posttranslational maturation of dystroglycan, our results demonstrate that the ligand-binding activity resides at the extreme N terminus of mature α-dystroglycan and is crucial for α-dystroglycan to coordinate the assembly of extracellular matrix proteins and to bind arenaviruses on the cell surface.

Large cystic tumour at the chest wall mimicking an echinococcosis: a case report.

The authors report an atypical late onset of a big axillary lymphatic malformation in a 41-year-old male. Considering the patient's history and clinical findings at first presentation, the swelling was highly suspicious for malignancy or cystic echinococcosis. A consequent CT showed non infiltrative growth with inhomogeneous density but remained non conclusive regarding diagnosis. Subsequently incision biopsy revealed lymphatic tissue and raised suspicion for lymphatic malformation. The tumour was excised completely and showed no recurrence in a 1-year follow up. Late onset lymphatic malformations can mimic malignant tumours or other rare conditions such as echinococcosis which has to be taken into consideration as differential diagnosis especially in known areas of hydatid diseases.

Climate oscillations and species interactions: large-scale congruence but regional differences in the phylogeographic structures of an alpine plant and its monophagous insect

Aim. To predict the fate of alpine interactions involving specialized species, using a monophagous beetle and its host-plant as a case study. Location. The Alps. Methods. We investigated genetic structuring of the herbivorous beetle Oreina gloriosa and its specific host-plant Peucedanum ostruthium. We used genome fingerprinting (in the insect and the plant) and sequence data (in the insect) to compare the distribution of the main gene pools in the two associated species and to estimate divergence time in the insect, a proxy for the temporal origin of the interaction. We quantified the similarity in spatial genetic structures by performing a Procrustes analysis, a tool from the shape theory. Finally, we simulated recolonization of an empty space analogous to the deglaciated Alps just after ice retreat by two lineages from two species showing unbalanced dependence, to examine how timing of the recolonization process, as well as dispersal capacities of associated species, could explain the observed pattern. Results. Contrasting with expectations based on their asymmetrical dependence, patterns in the beetle and plant were congruent at a large scale. Exceptions occurred at a regional scale in areas of admixture, matching known suture zones in Alpine plants. Simulations using a lattice-based model suggested these empirical patterns arose during or soon after recolonization, long after the estimated origin of the interaction c. 0.5 million years ago. Main conclusions. Species-specific interactions are scarce in alpine habitats because glacial cycles have limited opportunities for coevolution. Their fate, however, remains uncertain under climate change. Here we show that whereas most dispersal routes are paralleled at large scale, regional incongruence implies that the destinies of the species might differ under changing climate. This may be a consequence of the host-dependence of the beetle that locally limits the establishment of dispersing insects.

La coordination des dirigeants économiques face à la financiarisation : gouvernance d'entreprise, relations industrielles et élites dirigeantes dans l'industrie suisse des machines, de l'électrotechnique et de la métallurgie (1970-2008)

Résumé Cette recherche analyse les transformations de la gouvernance d'entreprise et des relations industrielles entre 1970 et 2008 dans le contexte suisse, en mettant l'accent sur les changements survenus depuis les années 1990. Elle se centre sur le secteur de l'industrie des machines, de l'électrotechnique et de la métallurgie -noyau historique du capitalisme helvétique et principal employeur et exportateur industriel du pays - et discute l'hypothèse de la convergence des économies coordonnées vers le modèle libéral. Elle examine d'abord les formes de coordination hors-marché qui se sont consolidées entre les élites économiques suisses au cours de la période d'après-guerre. Les stratégies d'innovation incrémentale des grandes sociétés étaient soutenues par une gouvernance marquée par la faible pression des marchés des capitaux, en raison notamment de la forte concentration de l'actionnariat, de mécanismes protectionnistes en matière d'accès au contrôle des sociétés, ainsi que d'une grande interdépendance entre banques et entreprises. Cette interdépendance apparaît dans la forte densité du réseau d'interconnexions des Conseils d'administration, où les principales banques tiennent une place centrale. Le réseau met également en relation les sociétés du secteur entre elles, ainsi qu'avec des firmes actives sur d'autres marchés, ce qui témoigne de l'irréductibilité des stratégies industrielles à une pure logique de compétition centrée sur les marchés. Les stratégies à long terme du management peuvent également s'appuyer sur un système pacifié de relations industrielles, caractérisé par l'autorégulation des acteurs privés dans le cadre d'un partenariat social de branche entre des associations aux stratégies modérées, « néocorporatistes ». Nous analysons alors l'impact de la libéralisation et de la financiarisation de l'économie suisse sur la coordination des élites économiques durant les années 1990. Nous montrons que l'affirmation des fonds d'investissement a déstabilisé le système traditionnel de gouvernance d'entreprise. Ce dernier a ainsi été marqué par l'émergence d'un marché pour le contrôle de l'entreprise -fin du «capital patient » -, la dissolution de l'interdépendance entre banques et industries et plus globalement des formes de coordination hors-marché reposant sur le réseau d'interconnexions des Conseils d'administration, ainsi que par de profondes restructurations des grandes sociétés orientées vers la création de richesse pour les actionnaires. La recherche explore alors les logiques d'interactions entre la sphère de la gouvernance d'entreprise et celle des relations industrielles, l'affirmation du capital financier faisant pression sur le partenariat social dans le sens d'une flexibilisation et déréglementation du marché du travail. Par ailleurs, nous mettons en perspective le rôle central des élites dans le changement institutionnel. Loin de subir la pression des actionnaires, les préférences d'une nouvelle élite managériale au profil financier ont convergé avec les intérêts des investisseurs dans le processus de financiarisation. Ces préférences ont également participé à l'érosion du partenariat social de branche. Du côté syndical, l'émergence -ici aussi - d'une nouvelle élite, académique et issue de la gauche politique, au cours des années 1990, a remis en cause les recettes de l'ancienne génération de syndicalistes ouvriers. La principale association du secteur a ainsi diversifié ses registres d'action en investissant la sphère politique et en relativisant la paix absolue du travail, deux stratégies activement rejetées par le syndicat au cours du régime de croissance d'après-guerre. Tout en mettant la sociologie des élites au service d'une meilleure compréhension des processus de changement institutionnel dans les capitalismes contemporains, cette recherche souligne des logiques de changement différentes dans les sphères sous revue :changement disruptif dans la gouvernance d'entreprise, incrémentai dans les relations industrielles. L'analyse s'est appuyée sur le croisement de différentes méthodes : analyse documentaire, entretiens semi-directifs, analyse du parcours et profil des élites, analyse de réseau, études de cas.

Detection of recurrence of large-bowel carcinoma by radioimmunoassay of circulating carcinoembryonic antigen (C.E.A.).

The usefulness and limitations of the carcinoembryonic antigen (C.E.A.) radioimmunoassay for the evaluation of tumour resection and for the detection of tumour relapse were studied in patients with large-bowel carcinoma. The level of plasma-C.E.A. was determined before any treatment in a group of 101 patients with histologically proven adenocarcinoma of the colon and rectum. 71% of all patients and 63% of cases with localised tumour (Dukes A and B) had a preoperative C.E.A. value of 5 ng. per ml. or higher. This limit was reached by only 1 of 90 apparently healthy, non-smoking blood-donors. Among 45 patients for whom a complete tumour resection was reported, all patients except 5 showed a drop of C.E.A. to normal values after surgery. The 5 patients whose C.E.A. did not fall to below 5 ng. per ml. showed a subsequent rise in C.E.A. level and were all found later to have a tumour relapse. The results indicate that an incomplete drop of circulating C.E.A. level one month after surgery has a bad prognostic significance. 22 of these patients were followed up by repeated C.E.A. radioimmunoassay for several months after surgery. 8 showed a progressive increase in C.E.A. levels preceding clinical diagnosis of tumour relapse by two to ten months. 6 other patients showed a moderate increase in C.E.A. levels, suggesting a tumour relapse not yet clinically detectable. The remaining 8 patients showed no increase in C.E.A. level above 5 ng. per ml. and no clinical symptoms of relapse. The results demonstrate that relapses of colon and rectum carcinoma can be detected by increased C.E.A. levels months before the appearance of any clinical evidence.

Large scale assessment of regulatory evolution and transcriptome complexity in mammals

AbstractIn addition to genetic changes affecting the function of gene products, changes in gene expression have been suggested to underlie many or even most of the phenotypic differences among mammals. However, detailed gene expression comparisons were, until recently, restricted to closely related species, owing to technological limitations. Thus, we took advantage of the latest technologies (RNA-Seq) to generate extensive qualitative and quantitative transcriptome data for a unique collection of somatic and germline tissues from representatives of all major mammalian lineages (placental mammals, marsupials and monotremes) and birds, the evolutionary outgroup.In the first major project of my thesis, we performed global comparative analyses of gene expression levels based on these data. Our analyses provided fundamental insights into the dynamics of transcriptome change during mammalian evolution (e.g., the rate of expression change across species, tissues and chromosomes) and allowed the exploration of the functional relevance and phenotypic implications of transcription changes at a genome-wide scale (e.g., we identified numerous potentially selectively driven expression switches).In a second project of my thesis, which was also based on the unique transcriptome data generated in the context of the first project we focused on the evolution of alternative splicing in mammals. Alternative splicing contributes to transcriptome complexity by generating several transcript isoforms from a single gene, which can, thus, perform various functions. To complete the global comparative analysis of gene expression changes, we explored patterns of alternative splicing evolution. This work uncovered several general and unexpected patterns of alternative splicing evolution (e.g., we found that alternative splicing evolves extremely rapidly) as well as a large number of conserved alternative isoforms that may be crucial for the functioning of mammalian organs.Finally, the third and final project of my PhD consisted in analyzing in detail the unique functional and evolutionary properties of the testis by exploring the extent of its transcriptome complexity. This organ was previously shown to evolve rapidly both at the phenotypic and molecular level, apparently because of the specific pressures that act on this organ and are associated with its reproductive function. Moreover, my analyses of the amniote tissue transcriptome data described above, revealed strikingly widespread transcriptional activity of both functional and nonfunctional genomic elements in the testis compared to the other organs. To elucidate the cellular source and mechanisms underlying this promiscuous transcription in the testis, we generated deep coverage RNA-Seq data for all major testis cell types as well as epigenetic data (DNA and histone methylation) using the mouse as model system. The integration of these complete dataset revealed that meiotic and especially post-meiotic germ cells are the major contributors to the widespread functional and nonfunctional transcriptome complexity of the testis, and that this "promiscuous" spermatogenic transcription is resulting, at least partially, from an overall transcriptionally permissive chromatin state. We hypothesize that this particular open state of the chromatin results from the extensive chromatin remodeling that occurs during spermatogenesis which ultimately leads to the replacement of histones by protamines in the mature spermatozoa. Our results have important functional and evolutionary implications (e.g., regarding new gene birth and testicular gene expression evolution).Generally, these three large-scale projects of my thesis provide complete and massive datasets that constitute valuables resources for further functional and evolutionary analyses of mammalian genomes.