Deciphering the Emerging Complexities of Molecular Mechanisms at GWAS Loci

Genome-wide association studies (GWASs) have identified thousands of loci associated with hundreds of complex diseases and traits, and progress is being made toward elucidating the causal variants and genes underlying these associations. Functional characterization of mechanisms at GWAS loci is a multi-faceted challenge. Challenges include linkage disequilibrium and allelic heterogeneity at each locus, the noncoding nature of most loci, and the time and cost needed for experimentally evaluating the potential mechanistic contributions of genes and variants. As GWAS sample sizes increase, more loci are identified, and the complexities of individual loci emerge. Loci can consist of multiple association signals, each of which can reflect the influence of multiple variants, inseparable by association analyses. Each signal within a locus can influence the same or different target genes. Experimental studies of genes and variants can differ on the basis of cell type, cellular environment, or other context-specific variables. In this review, we describe the complexity of mechanisms at GWAS loci—including multiple signals, multiple variants, and/or multiple genes—and the implications these complexities hold for experimental study design and interpretation of GWAS mechanisms

Opportunistic Multi-sensor Fusion for Robust Navigation in Smart Environments

Proceedings of: Workshop on User-Centric Technologies and Applications (CONTEXTS 2011), Salamanca, April 6-8, 2011This paper presents the design of a navigation system for multiple autonomous robotic platforms. It performs multisensor fusion using a Monte Carlo Bayesian filter, and has been designed to maximize information acquisition. Apart from sensors equipped in the mobile platform, the system can dynamically integrate observations from friendly external sensing entities, increasing robustness and making it suitable for both indoor and outdoor operation. A multi-agent layer manages the information acquisition process, making it transparent for the core filtering solution. As a proof of concept, some preliminary results are presented over a real platform using the part of the system specialized in outdoor navigationThis work was supported in part by Projects CICYT TIN2008-06742-C02-02/TSI, CICYT TEC2008-06732-C02-02/TEC, CAM CONTEXTS (S2009/ TIC-1485) and DPS2008-07029-C02-02.publicad

Triplet superconductivity in quasi one-dimensional systems

We study a Hubbard hamiltonian, including a quite general nearest-neighbor interaction, parametrized by repulsion V, exchange interactions Jz, Jperp, bond-charge interaction X and hopping of pairs W. The case of correlated hopping, in which the hopping between nearest neighbors depends upon the occupation of the two sites involved, is also described by the model for sufficiently weak interactions. We study the model in one dimension with usual continuum-limit field theory techniques, and determine the phase diagram. For arbitrary filling, we find a very simple necessary condition for the existence of dominant triplet superconducting correlations at large distance in the spin SU(2) symmetric case: 4V+J<0. In the correlated hopping model, the three-body interaction should be negative for positive V. We also compare the predictions of this weak-coupling treatment with numerical exact results for the correlated-hopping model obtained by diagonalizing small chains, and using novel techniques to determine the opening of the spin gap.Comment: 8 pages, 3 figure

Ground-state phase diagram of the one-dimensional half-filled extended Hubbard model

We revisit the ground-state phase diagram of the one-dimensional half-filled extended Hubbard model with on-site (U) and nearest-neighbor (V) repulsive interactions. In the first half of the paper, using the weak-coupling renormalization-group approach (g-ology) including second-order corrections to the coupling constants, we show that bond-charge-density-wave (BCDW) phase exists for U \approx 2V in between charge-density-wave (CDW) and spin-density-wave (SDW) phases. We find that the umklapp scattering of parallel-spin electrons disfavors the BCDW state and leads to a bicritical point where the CDW-BCDW and SDW-BCDW continuous-transition lines merge into the CDW-SDW first-order transition line. In the second half of the paper, we investigate the phase diagram of the extended Hubbard model with either additional staggered site potential \Delta or bond alternation \delta. Although the alternating site potential \Delta strongly favors the CDW state (that is, a band insulator), the BCDW state is not destroyed completely and occupies a finite region in the phase diagram. Our result is a natural generalization of the work by Fabrizio, Gogolin, and Nersesyan [Phys. Rev. Lett. 83, 2014 (1999)], who predicted the existence of a spontaneously dimerized insulating state between a band insulator and a Mott insulator in the phase diagram of the ionic Hubbard model. The bond alternation \delta destroys the SDW state and changes it into the BCDW state (or Peierls insulating state). As a result the phase diagram of the model with \delta contains only a single critical line separating the Peierls insulator phase and the CDW phase. The addition of \Delta or \delta changes the universality class of the CDW-BCDW transition from the Gaussian transition into the Ising transition.Comment: 24 pages, 20 figures, published versio

Phase diagram of the one-dimensional extended attractive Hubbard model for large nearest-neighbor repulsion

We consider the extended Hubbard model with attractive on-site interaction U and nearest-neighbor repulsions V. We construct an effective Hamiltonian H_{eff} for hopping t<<V and arbitrary U<0. Retaining the most important terms, H_{eff} can be mapped onto two XXZ models, solved by the Bethe ansatz. The quantum phase diagram shows two Luttinger liquid phases and a region of phase separation between them. For density n<0.422 and U<-4, singlet superconducting correlations dominate at large distances. For some parameters, the results are in qualitative agreement with experiments in BaKBiO.Comment: 6 pages, 3 figures, submitted to Phys. Rev.

Elevated circulating and placental SPINT2 is associated with placental dysfunction

Biomarkers for placental dysfunction are currently lacking. We recently identified SPINT1 as a novel biomarker; SPINT2 is a functionally related placental protease inhibitor. This study aimed to characterise SPINT2 expression in placental insufficiency. Circulating SPINT2 was assessed in three prospective cohorts, collected at the following: (1) term delivery (n = 227), (2) 36 weeks (n = 364), and (3) 24–34 weeks’ (n = 294) gestation. SPINT2 was also measured in the plasma and placentas of women with established placental disease at preterm (p = 0.028; median = 2233 pg/mL vs. controls, median = 1644 pg/mL), or delivered a small-for-gestational-age infant (p = 0.002; median = 2109 pg/mL vs. controls, median = 1614 pg/mL). SPINT2 was elevated in the placentas of patients who required delivery for preterm preeclampsia (p = 0.025). Though inflammatory cytokines had no effect, hypoxia increased SPINT2 in cytotrophoblast stem cells, and its expression was elevated in the placental labyrinth of growth-restricted rats. These findings suggest elevated SPINT2 is associated with placental insufficiency

Open chromatin profiling in adipose tissue marks genomic regions with functional roles in cardiometabolic traits

Identifying the regulatory mechanisms of genome-wide association study (GWAS) loci affecting adipose tissue has been restricted due to limited characterization of adipose transcriptional regulatory elements. We profiled chromatin accessibility in three frozen human subcutaneous adipose tissue needle biopsies and preadipocytes and adipocytes from the Simpson Golabi-Behmel Syndrome (SGBS) cell strain using an assay for transposase-accessible chromatin (ATAC-seq). We identified 68,571 representative accessible chromatin regions (peaks) across adipose tissue samples (FDR, 5%). GWAS loci for eight cardiometabolic traits were enriched in these peaks (P, 0.005), with the strongest enrichment for waist-hip ratio. Of 110 recently described cardiometabolic GWAS loci colocalized with adipose tissue eQTLs, 59 loci had one or more variants overlapping an adipose tissue peak. Annotated variants at the SNX10 waist-hip ratio locus and the ATP2A1-SH2B1 body mass index locus showed allelic differences in regulatory assays. These adipose tissue accessible chromatin regions elucidate genetic variants that may alter adipose tissue function to impact cardiometabolic traits

Characterization of a Legionella pneumophila gene encoding a lipoprotein antigen

A prominent 19kDa surface antigen of Legionella pneumophila , cloned in Escherichia coli , was found to be intimately associated with peptidoglycan. The DNA region encoding this antigen was mapped on an 11.9kb plasmid by means of deletion analysis and transposon mutagenesis. PhoA + gene fusions, generated by Tn phoA insertions into this region, confirmed the presence of a gene encoding a secreted protein. PhoA + transposon insertions were also associated with loss of the 19 kDa antigen in immunoassay s using a monoclonal antibody (mAb1E9) and the replacement of the 19kDa antigen with larger fusion proteins in immunoblots using Legionella immune serum. A 1540bp PstI fragment carrying the gene was sequenced, and the open reading frame encoding the antigen was identified. The gene encodes a polypeptide 176 amino acid residues long and 18913Da in size. The presence of a signal sequence of 22 amino acids with a consensus sequence for cleavage by signal peptidase II indicates that the antigen is a lipoprotein, and striking similarity with peptidoglycan-associated lipoproteins (PALs) from E. coli (51% amino acid homology) and Haemophilus influenzae (55% homology) is noted. We conclude that the 19kDa antigen of L. pneumophila is the structural equivalent of the PAL found in other Gram-negative species and suggest that its post-translational acylation may explain its potency as an immunogen.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75712/1/j.1365-2958.1991.tb00824.x.pd

Concordance and factor structure of subthreshold positive symptoms in youth at clinical high risk for psychosis

Prevailing models of psychosis risk incorporate positive subthreshold symptoms as defining features of risk or transition to psychotic disorders. Despite this, relatively few studies have focused on characterizing longitudinal symptom features, such as prevalence, concordance and structure, which may aid in refining methods and enhancing classification and prediction efforts. The present study aimed to fill these gaps using longitudinal 24-month follow-up data from the well-characterized NAPLS-2 multi-site investigation of youth at clinical high risk (CHR) who had (n = 86) and had not (n = 268) transitioned to a threshold psychotic disorder since baseline. At baseline, among sub-delusional ideas, unusual thought content and suspicious/persecutory thinking were very common in CHR youth, and were highly concordant. Perceptual abnormalities (P4) were also common across youth regardless of symptom course and eventual transition to psychosis. Grandiose ideas were rare. Exploratory factor analysis extracted two constituent factors at multiple follow-up intervals, but there was marked instability in the structure over 24 months, and clear indicators for a single positive symptom factor. Together these findings support suggestions to combine sub-delusional symptoms into a single symptom category for classification purposes, in efforts to reduce clinical heterogeneity and ease measurement burden