A minimal model of partial synchrony

Acknowledgement We wish to acknowledge A. Pikovsky and M. Zaks for useful discussions. This work has been financially supported by the EU project COSMOS (642563).

A minimal model of partial synchrony

We wish to acknowledge A Pikovsky and M Zaks for useful discussions. This work has been financially supported by the EU project COSMOS (642563).

L'évaluation de l'action préventive en contexte d'imprévisibilité : les enjeux d'un projet de prévention des MTS/VIH/SIDA par les pairs, Amazonas, Brésil

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Development and Characterization of Monovalent and Bivalent RNA Aptamers Targeting the Common Pathway of Coagulation

Anticoagulant agents are commonly used drugs to reduce blood coagulation in acute and chronic clinical settings. Many of these drugs target the common pathway of coagulation because it is critical for thrombin generation and disruption of this portion of the pathway has profound effects on the hemostatic process. Currently available drugs for these indications struggle with balancing desired activity with immunogenicity and poor reversibility or irreversibility in the event of hemorrhage. While improvements are being made with the current drugs, new drugs with better therapeutic indices are needed for surgical intervention and chronic indications to prevent thrombosis from occurring.

A class of therapeutics known as aptamers may be able to meet the need for safer anticoagulant agents. Aptamer are short single-stranded RNA oligonucleotides that adopt specific secondary and tertiary structures based upon their sequence. They can be generated to both enzymes and cofactors because they derive their inhibitory activity by blocking protein-protein interactions, rather than active site inhibition. They inhibit their target proteins with a high level of specificity and bind with high affinity to their target. Additionally, they can be reversed using two different antidote approaches, specific oligonucleotide antidotes, or with cationic, “universal” antidotes. The reversal of their activity is both rapid and durable.

The ability of aptamers to be generated to cofactors has been conclusively proven by generating an aptamer targeting the common pathway coagulation cofactor, Factor V (FV). We developed two aptamers with anticoagulant ability that bind to both FV and FVa, the active cofactor. Both aptamers were truncated to smaller functional sizes and had specific point mutant aptamers developed for use as controls. The anticoagulant activity of both aptamer-mutant pairs was characterized using plasma-based clotting assays and whole blood assays. The mechanism of action resulting in anticoagulant activity was assessed for one aptamer. The aptamer was found to block FVa docking to membrane surfaces, a mechanism not previously observed in any of our other anticoagulant aptamers.

To explore development of aptamers as anticoagulant agents targeting the common pathway for surgical interventions, we fused two anticoagulant aptamers targeting Factor X and prothrombin into a single molecule. The bivalent aptamer was truncated to a minimal size while maintaining robust anticoagulant activity. Characterization of the bivalent aptamer in plasma-based clotting assays indicated we had generated a very robust anticoagulant therapeutic. Furthermore, we were able to simultaneously reverse the activity of both aptamers with a single oligonucleotide antidote. This rapid and complete reversal of anticoagulant activity is not available in the antithrombotic agents currently used in surgery.

A Search for a New Particle Decaying to Pairs of Weak Gauge Bosons with the ATLAS Detector

A search for new heavy resonances decaying to boson pairs (WZ, WW or ZZ) using 20.3 inverse femtobarns of proton-proton collision data at a center of mass energy of 8 TeV is presented. The data were recorded by the ATLAS detector at the Large Hadron Collider (LHC) in 2012. The analysis combines several search channels with the leptonic, semi-leptonic and fully hadronic final states. The diboson invariant mass spectrum is studied for local excesses above the Standard Model background prediction, and no significant excess is observed for the combined analysis. 95$\%$ confidence limits are set on the cross section times branching ratios for three signal models: an extended gauge model with a heavy W boson, a bulk Randall-Sundrum model with a spin-2 graviton, and a simplified model with a heavy vector triplet. Among the individual search channels, the fully-hadronic channel is predominantly presented where boson tagging technique and jet substructure cuts are used. Local excesses are found in the dijet mass distribution around 2 TeV, leading to a global significance of 2.5 standard deviations. This deviation from the Standard Model prediction results in many theory explanations, and the possibilities could be further explored using the LHC Run 2 data.

Levi-flat Minimal Hypersurfaces in Two-dimensional Complex Space Forms

The purpose of this article is to classify the real hypersurfaces in complex space forms of dimension 2 that are both Levi-flat and minimal. The main results are as follows: When the curvature of the complex space form is nonzero, there is a 1-parameter family of such hypersurfaces. Specifically, for each one-parameter subgroup of the isometry group of the complex space form, there is an essentially unique example that is invariant under this one-parameter subgroup. On the other hand, when the curvature of the space form is zero, i.e., when the space form is complex 2-space with its standard flat metric, there is an additional `exceptional' example that has no continuous symmetries but is invariant under a lattice of translations. Up to isometry and homothety, this is the unique example with no continuous symmetries.

Occurrence and Function of Hoogsteen Base Pairs in Nucleic Acids

Nucleic acids (DNA and RNA) play essential roles in the central dogma of biology for the storage and transfer of genetic information. The unique chemical and conformational structures of nucleic acids – the double helix composed of complementary Watson-Crick base pairs, provide the structural basis to carry out their biological functions. DNA double helix can dynamically accommodate Watson-Crick and Hoogsteen base-pairing, in which the purine base is flipped by ~180° degrees to adopt syn rather than anti conformation as in Watson-Crick base pairs. There is growing evidence that Hoogsteen base pairs play important roles in DNA replication, recognition, damage or mispair accommodation and repair. Here, we constructed a database for existing Hoogsteen base pairs in DNA duplexes by a structure-based survey from the Protein Data Bank, and structural analyses based on the resulted Hoogsteen structures revealed that Hoogsteen base pairs occur in a wide variety of biological contexts and can induce DNA kinking towards the major groove. As there were documented difficulties in modeling Hoogsteen or Watson-Crick by crystallography, we collaborated with the Richardsons’ lab and identified potential Hoogsteen base pairs that were mis-modeled as Watson-Crick base pairs which suggested that Hoogsteen can be more prevalent than it was thought to be. We developed solution NMR method combined with the site-specific isotope labeling to characterize the formation of, or conformational exchange with Hoogsteen base pairs in large DNA-protein complexes under solution conditions, in the absence of the crystal packing force. We showed that there are enhanced chemical exchange, potentially between Watson-Crick and Hoogsteen, at a sharp kink site in the complex formed by DNA and the Integration Host Factor protein. In stark contrast to B-form DNA, we found that Hoogsteen base pairs are strongly disfavored in A-form RNA duplex. Chemical modifications N1-methyl adenosine and N1-methyl guanosine that block Watson-Crick base-pairing, can be absorbed as Hoogsteen base pairs in DNA, but rather potently destabilized A-form RNA and caused helix melting. The intrinsic instability of Hoogsteen base pairs in A-form RNA endows the N1-methylation as a functioning post-transcriptional modification that was known to facilitate RNA folding, translation and potentially play roles in the epitranscriptome. On the other hand, the dynamic property of DNA that can accommodate Hoogsteen base pairs could be critical to maintaining the genome stability.

Désensibilisation morale et légitimation de l'intimidation entre pairs au secondaire

Cette thèse doctorale, qui prend la forme de quatre articles, est une étude corrélationnelle mettant en relation le raisonnement moral et la légitimation des dynamiques d’intimidation par les pairs chez des adolescents de 3ème secondaire. L’objectif principal poursuivi était d’examiner la contribution de la désensibilisation morale aux conduites adoptées par les adolescents lors d’incidents d’intimidation à l’école. L’objectif secondaire était d’examiner l’importance accordée respectivement à des standards de conduite issus des domaines moral, conventionnel et personnel chez les adolescents impliqués dans des incidents d’intimidation. Le premier article expose la problématique de la légitimation des dynamiques d’intimidation par les jeunes en faisant état des croyances normatives et des caractéristiques des environnements scolaires qui y sont associées. L’article discute de l’écart qui s’observe entre l’opposition affirmée de la majorité des adolescents face aux conduites d’intimidation et leur récurrence dans les milieux scolaires et vient compléter une première section décrivant les conséquences de l’intimidation pour les communautés scolaires. Le deuxième article s’inscrit dans le cadre théorique de cette thèse et fait état des connaissances sur le raisonnement moral des élèves impliqués dans des dynamiques d’intimidation. Il présente une explication des conduites d’intimidation dans la perspective de la théorie des domaines de la connaissance sociale et dans celle de la théorie de l’agentivité morale. Ces approches ont été retenues pour opérationnaliser le concept de désensibilisation morale afin de rencontrer les objectifs de recherche poursuivis. Le troisième article rapporte la démarche utilisée pour vérifier l’hypothèse d’une relation positive entre les conduites d’intimidation et l’acceptabilité d’incidents d’intimidation hypothétiques, de même que l’hypothèse d’une relation positive entre les conduites d’intimidation et le désengagement moral chez les adolescents impliqués. Le quatrième article rapporte la démarche utilisée pour examiner les justifications sociomorales émises par différents profils d’adolescents impliqués dans des incidents d’intimidation de façon à associer leur conduite avec les domaines de connaissances normatives auxquels se rattachent leurs justifications. Les résultats obtenus sont ensuite discutés au chapitre suivant afin de mettre en évidence la contribution de chacune des approches morales retenues à l’explication des conduites en contexte d’intimidation et les caractéristiques du raisonnement moral associées aux rôles adoptés et des pistes d’intervention sont offertes. Finalement, cette thèse doctorale conclue que seul le niveau moyen de désengagement moral, un indice global de l’adhésion à des croyances normatives antisociales, contribue statistiquement à l’explication des conduites adoptées lors d’incident d’intimidation au-delà du sexe des participants. Quant au raisonnement sociomoral, il informe davantage sur la façon dont les circonstances d’incidents d’intimidation sont reliées à la désensibilisation morale des jeunes impliqués. Les adolescents qui prennent activement la défense de pairs intimidés étaient caractérisés par un raisonnement moral plus uniforme, tandis que le raisonnement des élèves qui intimident et de ceux qui demeurent passifs était caractérisé par la subordination de principes moraux, respectivement en faveur d’impératifs à caractère conventionnel et d’impératifs à caractère personnel.

L'évaluation de l'action préventive en contexte d'imprévisibilité : les enjeux d'un projet de prévention des MTS/VIH/SIDA par les pairs, Amazonas, Brésil

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Breeding success and traits of equal and unequal pairs of little penguins (Eudyptula minor) on Phillip Island during 2001-2008

According to life-history theory, individuals optimize their decisions in order to maximize their fitness. This raises a conflict between parents, which need to cooperate to ensure the propagation of their genes but at the same time need to minimize the associated costs. Trading-off between benefits and costs of a reproduction is one of the major forces driving demographic trends and has shaped several different parental care strategies. Using little penguins (Eudyptula minor) as a model, we investigated whether individuals of a pair provide equal parental effort when raising offspring and whether their behavior was consistent over 8 years of contrasting resource availability. Using an automated identification system, we found that 72% of little penguin pairs exhibited unforced (i.e., that did not result from desertion of 1 parent) unequal partnership through the postguard stage. This proportion was lower in favorable years. Although being an equal pair appeared to be a better strategy, it was nonetheless the least often observed. Individuals that contributed less than their partner were not less experienced (measured by age), and gender did not explain differences between partners. Furthermore, birds that contributed little or that contributed a lot tended to be consistent in their level of contribution across years. We suggest that unequal effort during breeding may reflect differences in individual quality, and we encourage future studies on parental care to consider this consistent low and high contributor behavior when investigating differences in pair investment into its offspring. Key words: attendance patterns, individual quality, meal size, parental care, reproductive costs, seabirds.

(Table 1) AMS-14C ages determined in pairs of spreiten and directly adjacent host sediment of cores M39029-4 and M29039-8

he downward transport of surface sediment deep into the sediment column by the Zoophycos-producing animal leads not only to large age differences between the Zoophycos structure and surrounding host sediment but also to large differences in age between different foraminifer species found inside the trace fossil. In the late Quaternary material from the southwestern Portuguese continental slope examined in this study, age differences of up to 2590 years were observed between the planktic foraminifer species Globigerinoides ruber and Globigerina bulloides. These differences are caused by the mixing of surface and host material with different abundances of the two species. If there are differences in the abundance of the two species at the surface and/or in the host sediment, plenty of relatively young foraminifers may be mixed with few relatively old ones, or vice versa. The age differences between species caused by the combination of deep-reaching bioturbation by the Zoophycos producer and abundance variations may be considerably larger than the age differences caused by the homogenizing bioturbation in the mixed layer.

Application of self-quenched JH consensus primers for real-time quantitative PCR of IGH gene to minimal residual disease evaluation in multiple myeloma.

Monitoring multiple myeloma patients for relapse requires sensitive methods to measure minimal residual disease and to establish a more precise prognosis. The present study aimed to standardize a real-time quantitative polymerase chain reaction (PCR) test for the IgH gene with a JH consensus self-quenched fluorescence reverse primer and a VDJH or DJH allele-specific sense primer (self-quenched PCR). This method was compared with allele-specific real-time quantitative PCR test for the IgH gene using a TaqMan probe and a JH consensus primer (TaqMan PCR). We studied nine multiple myeloma patients from the Spanish group treated with the MM2000 therapeutic protocol. Self-quenched PCR demonstrated sensitivity of >or=10(-4) or 16 genomes in most cases, efficiency was 1.71 to 2.14, and intra-assay and interassay reproducibilities were 1.18 and 0.75%, respectively. Sensitivity, efficiency, and residual disease detection were similar with both PCR methods. TaqMan PCR failed in one case because of a mutation in the JH primer binding site, and self-quenched PCR worked well in this case. In conclusion, self-quenched PCR is a sensitive and reproducible method for quantifying residual disease in multiple myeloma patients; it yields similar results to TaqMan PCR and may be more effective than the latter when somatic mutations are present in the JH intronic primer binding site.