Electronic couplings and on-site energies for hole transfer in DNA: systematic quantum mechanical/molecular dynamic study

The electron hole transfer (HT) properties of DNA are substantially affected by thermal fluctuations of the π stack structure. Depending on the mutual position of neighboring nucleobases, electronic coupling V may change by several orders of magnitude. In the present paper, we report the results of systematic QM/molecular dynamic (MD) calculations of the electronic couplings and on-site energies for the hole transfer. Based on 15 ns MD trajectories for several DNA oligomers, we calculate the average coupling squares 〈 V2 〉 and the energies of basepair triplets X G+ Y and X A+ Y, where X, Y=G, A, T, and C. For each of the 32 systems, 15 000 conformations separated by 1 ps are considered. The three-state generalized Mulliken-Hush method is used to derive electronic couplings for HT between neighboring basepairs. The adiabatic energies and dipole moment matrix elements are computed within the INDO/S method. We compare the rms values of V with the couplings estimated for the idealized B -DNA structure and show that in several important cases the couplings calculated for the idealized B -DNA structure are considerably underestimated. The rms values for intrastrand couplings G-G, A-A, G-A, and A-G are found to be similar, ∼0.07 eV, while the interstrand couplings are quite different. The energies of hole states G+ and A+ in the stack depend on the nature of the neighboring pairs. The X G+ Y are by 0.5 eV more stable than X A+ Y. The thermal fluctuations of the DNA structure facilitate the HT process from guanine to adenine. The tabulated couplings and on-site energies can be used as reference parameters in theoretical and computational studies of HT processes in DNA

Principal components of functional connectivity: A new approach to study dynamic brain connectivity during rest.

Functional connectivity (FC) as measured by correlation between fMRI BOLD time courses of distinct brain regions has revealed meaningful organization of spontaneous fluctuations in the resting brain. However, an increasing amount of evidence points to non-stationarity of FC; i.e., FC dynamically changes over time reflecting additional and rich information about brain organization, but representing new challenges for analysis and interpretation. Here, we propose a data-driven approach based on principal component analysis (PCA) to reveal hidden patterns of coherent FC dynamics across multiple subjects. We demonstrate the feasibility and relevance of this new approach by examining the differences in dynamic FC between 13 healthy control subjects and 15 minimally disabled relapse-remitting multiple sclerosis patients. We estimated whole-brain dynamic FC of regionally-averaged BOLD activity using sliding time windows. We then used PCA to identify FC patterns, termed "eigenconnectivities", that reflect meaningful patterns in FC fluctuations. We then assessed the contributions of these patterns to the dynamic FC at any given time point and identified a network of connections centered on the default-mode network with altered contribution in patients. Our results complement traditional stationary analyses, and reveal novel insights into brain connectivity dynamics and their modulation in a neurodegenerative disease.

Dynamic regulation of notch 1 and notch 2 surface expression during T cell development and activation revealed by novel monoclonal antibodies.

It is well established that Notch signaling plays a critical role at multiple stages of T cell development and activation. However, detailed analysis of the cellular and molecular events associated with Notch signaling in T cells is hampered by the lack of reagents that can unambiguously measure cell surface Notch receptor expression. Using novel rat mAbs directed against the extracellular domains of Notch1 and Notch2, we find that Notch1 is already highly expressed on common lymphoid precursors in the bone marrow and remains at high levels during intrathymic maturation of CD4(-)CD8(-) thymocytes. Notch1 is progressively down-regulated at the CD4(+)CD8(+) and mature CD4(+) or CD8(+) thymic stages and is expressed at low levels on peripheral T cells. Immunofluorescence staining of thymus cryosections further revealed a localization of Notch1(+)CD25(-) cells adjacent to the thymus capsule. Notch1 was up-regulated on peripheral T cells following activation in vitro with anti-CD3 mAbs or infection in vivo with lymphocytic chorio-meningitis virus or Leishmania major. In contrast to Notch1, Notch2 was expressed at intermediate levels on common lymphoid precursors and CD117(+) early intrathymic subsets, but disappeared completely at subsequent stages of T cell development. However, transient up-regulation of Notch2 was also observed on peripheral T cells following anti-CD3 stimulation. Collectively our novel mAbs reveal a dynamic regulation of Notch1 and Notch2 surface expression during T cell development and activation. Furthermore they provide an important resource for future analysis of Notch receptors in various tissues including the hematopoietic system.

New Radicals and new applications of Dynamic Nuclear Polarization of biological systems

Dynamic Nuclear Polarization (DNP) is an emerging technique that could revolutionize the NMR study of small molecules at very low concentrations by the increase in sensitivity that results from transfer of polarization between electronic and nuclear spins. Although the underlying physics has been known for a long time, in the last few years there has been a lot of excitement on the chemistry and biology NMR community caused by the demonstration that the highly polarized nuclei that are prepared in solid state at very low temperatures (1-2 K) could be rapidly transferred to liquid samples at room temperature and studied in solution by conventional NMR techniques. In favorable cases several order of magnitude increases in sensitivity have been achieved. The technique is now mature enough that a commercial instrument is available. The efficiency of DNP depends on two crucial aspects: i) the efficiency of the nuclear polarization process and ii) the efficiency of the transfer from the initial solid state to the fluid state in which NMR is measured. The preferred areas of application (iii) will be dictated by situations in which the low concentration of the sample or its intrinsic low receptivity are the limiting factors .

Developing methodologies to allow the robust prediction dynamic context dominated by perturbations

El principal objectiu del projecte era desenvolupar millores conceptuals i metodològiques que permetessin una millor predicció dels canvis en la distribució de les espècies (a una escala de paisatge) derivats de canvis ambientals en un context dominat per pertorbacions. En un primer estudi, vàrem comparar l'eficàcia de diferents models dinàmics per a predir la distribució de l'hortolà (Emberiza hortulana). Els nostres resultats indiquen que un model híbrid que combini canvis en la qualitat de l'hàbitat, derivats de canvis en el paisatge, amb un model poblacional espacialment explícit és una aproximació adequada per abordar canvis en la distribució d'espècies en contextos de dinàmica ambiental elevada i una capacitat de dispersió limitada de l'espècie objectiu. En un segon estudi abordarem la calibració mitjançant dades de seguiment de models de distribució dinàmics per a 12 espècies amb preferència per hàbitats oberts. Entre les conclusions extretes destaquem: (1) la necessitat de que les dades de seguiment abarquin aquelles àrees on es produeixen els canvis de qualitat; (2) el biaix que es produeix en la estimació dels paràmetres del model d'ocupació quan la hipòtesi de canvi de paisatge o el model de qualitat d'hàbitat són incorrectes. En el darrer treball estudiarem el possible impacte en 67 espècies d’ocells de diferents règims d’incendis, definits a partir de combinacions de nivells de canvi climàtic (portant a un augment esperat de la mida i freqüència d’incendis forestals), i eficiència d’extinció per part dels bombers. Segons els resultats dels nostres models, la combinació de factors antropogènics del regim d’incendis, tals com l’abandonament rural i l’extinció, poden ser més determinants per als canvis de distribució que els efectes derivats del canvi climàtic. Els productes generats inclouen tres publicacions científiques, una pàgina web amb resultats del projecte i una llibreria per a l'entorn estadístic R.

Assembling genes from predicted exons in linear time with dynamic programming

In a number of programs for gene structure prediction in higher eukaryotic genomic sequences, exon prediction is decoupled from gene assembly: a large pool of candidate exons is predicted and scored from features located in the query DNA sequence, and candidate genes are assembled from such a pool as sequences of nonoverlapping frame-compatible exons. Genes are scored as a function of the scores of the assembled exons, and the highest scoring candidate gene is assumed to be the most likely gene encoded by the query DNA sequence. Considering additive gene scoring functions, currently available algorithms to determine such a highest scoring candidate gene run in time proportional to the square of the number of predicted exons. Here, we present an algorithm whose running time grows only linearly with the size of the set of predicted exons. Polynomial algorithms rely on the fact that, while scanning the set of predicted exons, the highest scoring gene ending in a given exon can be obtained by appending the exon to the highest scoring among the highest scoring genes ending at each compatible preceding exon. The algorithm here relies on the simple fact that such highest scoring gene can be stored and updated. This requires scanning the set of predicted exons simultaneously by increasing acceptor and donor position. On the other hand, the algorithm described here does not assume an underlying gene structure model. Indeed, the definition of valid gene structures is externally defined in the so-called Gene Model. The Gene Model specifies simply which gene features are allowed immediately upstream which other gene features in valid gene structures. This allows for great flexibility in formulating the gene identification problem. In particular it allows for multiple-gene two-strand predictions and for considering gene features other than coding exons (such as promoter elements) in valid gene structures.

Dynamic estimation of three-dimensional cerebrovascular deformation from rotational angiography

Purpose: The objective of this study is to investigate the feasibility of detecting and quantifying 3D cerebrovascular wall motion from a single 3D rotational x-ray angiography (3DRA) acquisition within a clinically acceptable time and computing from the estimated motion field for the further biomechanical modeling of the cerebrovascular wall. Methods: The whole motion cycle of the cerebral vasculature is modeled using a 4D B-spline transformation, which is estimated from a 4D to 2D + t image registration framework. The registration is performed by optimizing a single similarity metric between the entire 2D + t measured projection sequence and the corresponding forward projections of the deformed volume at their exact time instants. The joint use of two acceleration strategies, together with their implementation on graphics processing units, is also proposed so as to reach computation times close to clinical requirements. For further characterizing vessel wall properties, an approximation of the wall thickness changes is obtained through a strain calculation. Results: Evaluation on in silico and in vitro pulsating phantom aneurysms demonstrated an accurate estimation of wall motion curves. In general, the error was below 10% of the maximum pulsation, even in the situation when substantial inhomogeneous intensity pattern was present. Experiments on in vivo data provided realistic aneurysm and vessel wall motion estimates, whereas in regions where motion was neither visible nor anatomically possible, no motion was detected. The use of the acceleration strategies enabled completing the estimation process for one entire cycle in 5-10 min without degrading the overall performance. The strain map extracted from our motion estimation provided a realistic deformation measure of the vessel wall. Conclusions: The authors' technique has demonstrated that it can provide accurate and robust 4D estimates of cerebrovascular wall motion within a clinically acceptable time, although it has to be applied to a larger patient population prior to possible wide application to routine endovascular procedures. In particular, for the first time, this feasibility study has shown that in vivo cerebrovascular motion can be obtained intraprocedurally from a 3DRA acquisition. Results have also shown the potential of performing strain analysis using this imaging modality, thus making possible for the future modeling of biomechanical properties of the vascular wall.

LdShake: learning design solutions sharing and co-edition

Two important challenges that teachers are currently facing are the sharing and the collaborative authoring of their learning design solutions, such as didactical units and learning materials. On the one hand, there are tools that can be used for the creation of design solutions and only some of them facilitate the co-edition. However, they do not incorporate mechanisms that support the sharing of the designs between teachers. On the other hand, there are tools that serve as repositories of educational resources but they do not enable the authoring of the designs. In this paper we present LdShake, a web tool whose novelty is focused on the combined support for the social sharing and co-edition of learning design solutions within communities of teachers. Teachers can create and share learning designs with other teachers using different access rights so that they can read, comment or co-edit the designs. Therefore, each design solution is associated to a group of teachers able to work on its definition, and another group that can only see the design. The tool is generic in that it allows the creation of designs based on any pedagogical approach. However, it can be particularized in instances providing pre-formatted designs structured according to a specific didactic method (such as Problem-Based Learning, PBL). A particularized LdShake instance has been used in the context of Human Biology studies where teams of teachers are required to work together in the design of PBL solutions. A controlled user study, that compares the use of a generic LdShake and a Moodle system, configured to enable the creation and sharing of designs, has been also carried out. The combined results of the real and controlled studies show that the social structure, and the commenting, co-edition and publishing features of LdShake provide a useful, effective and usable approach for facilitating teachers' teamwork.

On codes, matroids, and secure multiparty computation from linear secret-sharing schemes

Error-correcting codes and matroids have been widely used in the study of ordinary secret sharing schemes. In this paper, the connections between codes, matroids, and a special class of secret sharing schemes, namely, multiplicative linear secret sharing schemes (LSSSs), are studied. Such schemes are known to enable multiparty computation protocols secure against general (nonthreshold) adversaries.Two open problems related to the complexity of multiplicative LSSSs are considered in this paper. The first one deals with strongly multiplicative LSSSs. As opposed to the case of multiplicative LSSSs, it is not known whether there is an efficient method to transform an LSSS into a strongly multiplicative LSSS for the same access structure with a polynomial increase of the complexity. A property of strongly multiplicative LSSSs that could be useful in solving this problem is proved. Namely, using a suitable generalization of the well-known Berlekamp–Welch decoder, it is shown that all strongly multiplicative LSSSs enable efficient reconstruction of a shared secret in the presence of malicious faults. The second one is to characterize the access structures of ideal multiplicative LSSSs. Specifically, the considered open problem is to determine whether all self-dual vector space access structures are in this situation. By the aforementioned connection, this in fact constitutes an open problem about matroid theory, since it can be restated in terms of representability of identically self-dual matroids by self-dual codes. A new concept is introduced, the flat-partition, that provides a useful classification of identically self-dual matroids. Uniform identically self-dual matroids, which are known to be representable by self-dual codes, form one of the classes. It is proved that this property also holds for the family of matroids that, in a natural way, is the next class in the above classification: the identically self-dual bipartite matroids.

Multiuser detection in a dynamic environment — Part II: Joint user identification and parameter estimation

The problem of jointly estimating the number, the identities, and the data of active users in a time-varying multiuser environment was examined in a companion paper (IEEE Trans. Information Theory, vol. 53, no. 9, September 2007), at whose core was the use of the theory of finite random sets on countable spaces. Here we extend that theory to encompass the more general problem of estimating unknown continuous parameters of the active-user signals. This problem is solved here by applying the theory of random finite sets constructed on hybrid spaces. We doso deriving Bayesian recursions that describe the evolution withtime of a posteriori densities of the unknown parameters and data.Unlike in the above cited paper, wherein one could evaluate theexact multiuser set posterior density, here the continuous-parameter Bayesian recursions do not admit closed-form expressions. To circumvent this difficulty, we develop numerical approximationsfor the receivers that are based on Sequential Monte Carlo (SMC)methods (“particle filtering”). Simulation results, referring to acode-divisin multiple-access (CDMA) system, are presented toillustrate the theory.

Stochastic Dynamic Northern Corn Rootworm Population Model, January 2000

A complete life cycle model for northern corn rootworm, Diabrotica barberi Smith and Lawrence, is developed using a published single-season model of adult population dynamics and data from field experiments. Temperature-dependent development and age-dependent advancement determine adult population dynamics and oviposition, while a simple stochastic hatch and density-dependent larval survival model determine adult emergence. Dispersal is not modeled. To evaluate the long-run performance of the model, stochastically generated daily air and soil temperatures are used for 100-year simulations for a variety of corn planting and flowering dates in Ithaca, NY, and Brookings, SD. Once the model is corrected for a bias in oviposition, model predictions for both locations are consistent with anecdotal field data. Extinctions still occur, but these may be consistent with northern corn rootworm metapopulation dynamics.

Large-system analysis of a CDMA dynamic channel under a Markovian input process

We study the minimum mean square error (MMSE) and the multiuser efficiency η of large dynamic multiple access communication systems in which optimal multiuser detection is performed at the receiver as the number and the identities of active users is allowed to change at each transmission time. The system dynamics are ruled by a Markov model describing the evolution of the channel occupancy and a large-system analysis is performed when the number of observations grow large. Starting on the equivalent scalar channel and the fixed-point equation tying multiuser efficiency and MMSE, we extend it to the case of a dynamic channel, and derive lower and upper bounds for the MMSE (and, thus, for η as well) holding true in the limit of large signal–to–noise ratios and increasingly large observation time T.

Alliance patterns over the course of short-term dynamic psychotherapy: The shape of productive relationships.

The shape of alliance processes over the course of psychotherapy has already been studied in several process-outcome studies on very brief psychotherapy. The present study applies the shape-of-change methodology to short-term dynamic psychotherapies and complements this method with hierarchical linear modeling. A total of 50 psychotherapies of up to 40 sessions were included. Alliance was measured at the end of each session. The results indicate that a linear progression model is most adequate. Three main patterns were found: stable, linear, and quadratic growth. The linear growth pattern, along with the slope parameter, was related to treatment outcome. This study sheds additional light on alliance process research, underscores the importance of linear alliance progression for outcome, and also fosters a better understanding of its limitations.

Identity, immigration, and prejudice in Europe: a recognition approach

Social identity is a double-edged sword. On the one hand, identifying with a social group is a prerequisite for the sharing of common norms and values, solidarity, and collective action. On the other hand, in-group identification often goes together with prejudice and discrimination. Today, these two sides of social identification underlie contradictory trends in the way European nations and European nationals relate to immigrants and immigration. Most European countries are becoming increasingly multicultural, and anti-discrimination laws have been adopted throughout the European Union, demonstrating a normative shift towards more social inclusion and tolerance. At the same time, racist and xenophobic attitudes still shape social relations, individual as well as collective behaviour (both informal and institutional), and political positions throughout Europe. The starting point for this chapter is Sanchez-Mazas' (2004) interactionist approach to the study of racism and xenophobia, which in turn builds on Axel Honneth's (1996) philosophical theory of recognition. In this view, the origin of attitudes towards immigrants cannot be located in one or the other group, but in a dynamic of mutual influence. Sanchez-Mazas' approach is used as a general framework into which we integrate social psychological approaches of prejudice and recent empirical findings examining minority-majority relations. We particularly focus on the role of national and European identities as antecedents of anti-immigrant attitudes held by national majorities. Minorities' reactions to denials of recognition are also examined. We conclude by delineating possible social and political responses to prejudice towards immigrants.

Controlled dynamic generation of standard 1,6-hexamethylene diisocyanate aerosols

A procedure for the dynamic generation of 1,6-hexamethylene diisocyanate (HDI) aerosol atmospheres of 70 micrograms m-3 (0.01 ppm) to 1.75 mg m-3 (0.25 ppm), based on the precise control of the evaporation of pure liquid HDI and subsequent dilution with air, was developed. The apparatus consisted of a home-made glass nebulizer coupled with a separation stage to exclude non-respirable droplets (greater than 10 microns). The aerosol concentrations were achieved by passing air through the nebulizer at 1.5-4.5 l. min-1 to generate dynamically 0.01-0.25 ppm of diisocyanate in an experimental chamber of 8.55 m3. The distribution of the liquid aerosol was established with an optical counter and the diisocyanate concentration was determined from samples collected in impingers by a high-pressure liquid chromatographic method. The atmospheres generated were suitable for the evaluation both of sampling procedures full scale, and of analytical methods: at 140 micrograms m-3 (0.02 ppm) they remained stable for 15-min provocation tests in clinical asthma, as verified by breath-zone sampling of exposed patients.