Variational methods

International audienceThis contribution presents derivative-based methods for local sensitivity analysis, called Variational Sensitivity Analysis (VSA). If one defines an output called the response function, its sensitivity to inputs variations around a nominal value can be studied using derivative (gradient) information. The main issue of VSA is then to provide an efficient way of computing gradients. This contribution first presents the theoretical grounds of VSA: framework and problem statement, tangent and adjoint methods. Then it covers pratical means to compute derivatives, from naive to more sophisticated approaches, discussing their various 2 merits. Finally, applications of VSA are reviewed and some examples are presented, covering various applications fields: oceanography, glaciology, meteorology

Host genotype and time dependent antigen presentation of viral peptides: predictions from theory

The rate of progression of HIV infected individuals to AIDS is known to vary with the genotype of the host, and is linked to their allele of human leukocyte antigen (HLA) proteins, which present protein degradation products at the cell surface to circulating T-cells. HLA alleles are associated with Gag-specific T-cell responses that are protective against progression of the disease. While Pol is the most conserved HIV sequence, its association with immune control is not as strong. To gain a more thorough quantitative understanding of the factors that contribute to immunodominance, we have constructed a model of the recognition of HIV infection by the MHC class I pathway. Our model predicts surface presentation of HIV peptides over time, demonstrates the importance of viral protein kinetics, and provides evidence of the importance of Gag peptides in the long-term control of HIV infection. Furthermore, short-term dynamics are also predicted, with simulation of virion-derived peptides suggesting that efficient processing of Gag can lead to a 50% probability of presentation within 3 hours post-infection, as observed experimentally. In conjunction with epitope prediction algorithms, this modelling approach could be used to refine experimental targets for potential T-cell vaccines, both for HIV and other viruses

Relationship Contexts as Sources of Socialization: An Exploration of Intimate Partner Violence Experiences of Economically Disadvantaged African American Adolescents

Intimate partner violence (IPV) among African Americans is a serious public health concern. Research suggest that African Americans adolescents, particularly those from economically disadvantaged communities, are at heightened risk for experiencing and perpetrating dating violence compared to youth from other racial and ethnic groups. In the present study, we examined different relationship contexts that are sources of IPV socialization. Semi-structured interviews were conducted with 22 economically disadvantaged African American adolescents. Content analysis yielded five relationship contexts through which the participants witnessed, experienced, and perpetrated IPV: (a) adolescents’ own dating relationships (64%), (b) siblings and extended family members (e.g., cousins, aunts, uncles) (59%), (c) parent-partners (27%), (d) friends (23%), and (e) neighbors (18%). Adolescents also frequently described IPV in their own dating relationships and in parent-partner relationships as mutual. Moreover, they appeared to minimize the experience of IPV in their own relationships. Efforts to reduce rates of IPV among economically disadvantaged African American adolescents should consider these relational contexts through which adolescents are socialized with regards to IPV and adolescents’ beliefs about mutual violence in relationships. Results highlight the importance of culturally relevant prevention and intervention programs that consider these relationship contexts

Spatially and Financially Explicit Population Viability Analysis of Maculinea alcon in The Netherlands

Background The conservation of species structured in metapopulations involves an important dilemma of resource allocation: should investments be directed at restoring/enlarging habitat patches or increasing connectivity. This is still an open question for Maculinea species despite they are among the best studied and emblematic butterfly species, because none of the population dynamics models developed so far included dispersal. Methodology/Principal Findings We developed the first spatially and financially explicit Population Viability Analysis model for Maculinea alcon, using field data from The Netherlands. Implemented using the RAMAS/GIS platform, the model incorporated both local (contest density dependence, environmental and demographic stochasticities), and regional population dynamics (dispersal rates between habitat patches). We selected four habitat patch networks, contrasting in several basic features (number of habitat patches, their quality, connectivity, and occupancy rate) to test how these features are affecting the ability to enhance population viability of four basic management options, designed to incur the same costs: habitat enlargement, habitat quality improvement, creation of new stepping stone habitat patches, and reintroduction of captive-reared butterflies. The PVA model was validated by the close match between its predictions and independent field observations on the patch occupancy pattern. The four patch networks differed in their sensitivity to model parameters, as well as in the ranking of management options. Overall, the best cost-effective option was enlargement of existing habitat patches, followed by either habitat quality improvement or creation of stepping stones depending on the network features. Reintroduction was predicted to generally be inefficient, except in one specific patch network. Conclusions/Significance Our results underline the importance of spatial and regional aspects (dispersal and connectivity) in determining the impact of conservation actions, even for a species previously considered as sedentary. They also illustrate that failure to account for the cost of management scenarios can lead to very different conclusions

The neurogenic potential of astrocytes is regulated by inflammatory signals

Although the adult brain contains neural stem cells (NSCs) that generate new neurons throughout life, these astrocyte-like populations are restricted to two discrete niches. Despite their terminally differentiated phenotype, adult parenchymal astrocytes can re-acquire NSC-like characteristics following injury, and as such, these 'reactive' astrocytes offer an alternative source of cells for central nervous system (CNS) repair following injury or disease. At present, the mechanisms that regulate the potential of different types of astrocytes are poorly understood. We used in vitro and ex vivo astrocytes to identify candidate pathways important for regulation of astrocyte potential. Using in vitro neural progenitor cell (NPC)-derived astrocytes, we found that exposure of more lineage-restricted astrocytes to either tumor necrosis factor alpha (TNF-α) (via nuclear factor-κB (NFκB)) or the bone morphogenetic protein (BMP) inhibitor, noggin, led to re-acquisition of NPC properties accompanied by transcriptomic and epigenetic changes consistent with a more neurogenic, NPC-like state. Comparative analyses of microarray data from in vitro-derived and ex vivo postnatal parenchymal astrocytes identified several common pathways and upstream regulators associated with inflammation (including transforming growth factor (TGF)-β1 and peroxisome proliferator-activated receptor gamma (PPARγ)) and cell cycle control (including TP53) as candidate regulators of astrocyte phenotype and potential. We propose that inflammatory signalling may control the normal, progressive restriction in potential of differentiating astrocytes as well as under reactive conditions and represent future targets for therapies to harness the latent neurogenic capacity of parenchymal astrocytes

Systematic Evaluation of Pleiotropy Identifies 6 Further Loci Associated With Coronary Artery Disease

Background: Genome-wide association studies have so far identified 56 loci associated with risk of coronary artery disease (CAD). Many CAD loci show pleiotropy; that is, they are also associated with other diseases or traits. Objectives: This study sought to systematically test if genetic variants identified for non-CAD diseases/traits also associate with CAD and to undertake a comprehensive analysis of the extent of pleiotropy of all CAD loci. Methods: In discovery analyses involving 42,335 CAD cases and 78,240 control subjects we tested the association of 29,383 common (minor allele frequency >5%) single nucleotide polymorphisms available on the exome array, which included a substantial proportion of known or suspected single nucleotide polymorphisms associated with common diseases or traits as of 2011. Suggestive association signals were replicated in an additional 30,533 cases and 42,530 control subjects. To evaluate pleiotropy, we tested CAD loci for association with cardiovascular risk factors (lipid traits, blood pressure phenotypes, body mass index, diabetes, and smoking behavior), as well as with other diseases/traits through interrogation of currently available genome-wide association study catalogs. Results: We identified 6 new loci associated with CAD at genome-wide significance: on 2q37 (KCNJ13-GIGYF2), 6p21 (C2), 11p15 (MRVI1-CTR9), 12q13 (LRP1), 12q24 (SCARB1), and 16q13 (CETP). Risk allele frequencies ranged from 0.15 to 0.86, and odds ratio per copy of the risk allele ranged from 1.04 to 1.09. Of 62 new and known CAD loci, 24 (38.7%) showed statistical association with a traditional cardiovascular risk factor, with some showing multiple associations, and 29 (47%) showed associations at p < 1 × 10−4 with a range of other diseases/traits. Conclusions: We identified 6 loci associated with CAD at genome-wide significance. Several CAD loci show substantial pleiotropy, which may help us understand the mechanisms by which these loci affect CAD risk

Lack of seasonal variation in idiopathic talipes equinovarus.

BACKGROUND: One proposed etiology of idiopathic talipes equinovarus is an in utero enterovirus infection. Enterovirus infections demonstrate seasonal variation in temperate climates. METHODS: We collected data on 1202 children with idiopathic talipes equinovarus born in the Northeastern United States, Midwestern United States, and the United Kingdom to investigate a seasonal variation in this congenital deformity. Birth date, gestational age at the time of delivery, gender, race, and laterality were tabulated and subjected to univariate and bivariate analyses. RESULTS: There were 774 boys and 428 girls with idiopathic talipes equinovarus. The birth location was the United Kingdom (458 children), the Midwestern United States (426 children), and the Northeastern United States (318 children). No significant differences were detected among the geographic groups with respect to gender, race, or laterality, and no variation in month of birth or month of conception was noted. CONCLUSIONS: This study does not support an in utero enterovirus infection as an etiology of idiopathic talipes equinovarus in industrialized populations