Risk patterns and correlated brain activities. Multidimensional statistical analysis of FMRI data in economic decision making study

Decision making usually involves uncertainty and risk. Understanding which parts of the human brain are activated during decisions under risk and which neural processes underly (risky) investment decisions are important goals in neuroeconomics. Here, we analyze functional magnetic resonance imaging (fMRI) data on 17 subjects who were exposed to an investment decision task from Mohr, Biele, Krugel, Li, and Heekeren (in NeuroImage 49, 2556–2563, 2010b). We obtain a time series of three-dimensional images of the blood-oxygen-level dependent (BOLD) fMRI signals. We apply a panel version of the dynamic semiparametric factor model (DSFM) presented in Park, Mammen, Wolfgang, and Borak (in Journal of the American Statistical Association 104(485), 284–298, 2009) and identify task-related activations in space and dynamics in time. With the panel DSFM (PDSFM) we can capture the dynamic behavior of the specific brain regions common for all subjects and represent the high-dimensional time-series data in easily interpretable low-dimensional dynamic factors without large loss of variability. Further, we classify the risk attitudes of all subjects based on the estimated low-dimensional time series. Our classification analysis successfully confirms the estimated risk attitudes derived directly from subjects’ decision behavior

Quantification of large and middle proteins of hepatitis B virus surface antigen (HBsAg) as a novel tool for the identification of inactive HBV carriers

Objective Among individuals with chronic hepatitis B, those with hepatitis B e-antigen (HBeAg)-negative chronic hepatitis (CHB) can be difficult to distinguish from those with HBeAg-negative chronic HBV infection, also referred to as inactive HBV carriers (ICs), but both require different medical management. The level of HBV surface antigen (HBsAg) has been proposed as a marker to discriminate between chronic infection and hepatitis stages. HBsAg consists of large, middle and small HBs. The aim of this study was to determine whether the composition of HBsAg improved the identification of ICs among HBsAg-positive subjects with different phases of HBV infections. Design HBV large surface proteins (LHBs) and HBV middle surface proteins (MHBs) were quantified in serum samples from 183 clinically well-characterised untreated patients with acute (n=14) HBV infection, ICs (n=44), CHBs (n=46), chronic HBeAg-positive phase (n=68) and hepatitis delta coinfection (n=11) using an ELISA, with well-defined monoclonal antibodies against the preS1 domain (LHBs) and the preS2-domain (MHBs). A Western blot analysis was used to verify the quantitation of the components of HBsAg. Total HBsAg was quantified using a modified commercially available assay (HBsAg V. 6.0, Enzygnost, Siemens, Erlangen). Results The composition of HBsAg showed specific patterns across different phases of hepatitis B. Individuals in the IC phase had significantly lower proportions of LHBs and MHBs than patients in acute or chronic phases irrespective of their HBV e-antigen status (p< 0.0001) or HBsAg level. Both LHBs and MHBs ratios better predicted the IC phase than total HBsAg levels. Conclusion Quantification of MHBs, particularly LHBs represents a novel tool for the identification of the IC stage

Coherence effect in a two-band superconductor: Application to iron pnictides

From a theoretical point of view, we propose an experimental method to determine the pairing symmetry of iron pnictides. We focus on two kinds of pairing symmetries, $s_{+-}$ and $s_{++}$, which are strong candidates for the pairing symmetry of iron pnictides. For each of these two symmetries, we calculate both the density and spin response functions by using the two-band BCS model within the one-loop approximation. As a result, a clear difference is found between the $s_{+-}$- and $s_{++}$-wave states in the temperature dependence of the response functions at nesting vector $\bf{Q}$, which connects the hole and electron Fermi surfaces. We point out that this difference comes from the coherence effect in the two-band superconductor. We suggest that the pairing symmetry could be clarified by observing the temperature dependence of both the density and spin structure factors at the nesting vector $\bf{Q}$ in neutron scattering measurements.Comment: 15 pages, 7 figures, 1 tabl

The crossover from propagating to strongly scattered acoustic modes of glasses observed in densified silica

Spectroscopic results on low frequency excitations of densified silica are presented and related to characteristic thermal properties of glasses. The end of the longitudinal acoustic branch is marked by a rapid increase of the Brillouin linewidth with the scattering vector. This rapid growth saturates at a crossover frequency Omega_co which nearly coincides with the center of the boson peak. The latter is clearly due to additional optic-like excitations related to nearly rigid SiO_4 librations as indicated by hyper-Raman scattering. Whether the onset of strong scattering is best described by hybridization of acoustic modes with these librations, by their elastic scattering (Rayleigh scattering) on the local excitations, or by soft potentials remains to be settled.Comment: 14 pages, 6 figures, to be published in a special issue of J. Phys. Condens. Matte

Nitration of the Egg-Allergen Ovalbumin Enhances Protein Allergenicity but Reduces the Risk for Oral Sensitization in a Murine Model of Food Allergy

Nitration of proteins on tyrosine residues, which can occur due to polluted air under "summer smog" conditions, has been shown to increase the allergic potential of allergens. Since nitration of tyrosine residues is also observed during inflammatory responses, this modification could directly influence protein immunogenicity and might therefore contribute to food allergy induction. In the current study we have analyzed the impact of protein nitration on sensitization via the oral route.BALB/c mice were immunized intragastrically by feeding untreated ovalbumin (OVA), sham-nitrated ovalbumin (snOVA) or nitrated ovalbumin (nOVA) with or without concomitant acid-suppression. To analyze the impact of the sensitization route, the allergens were also injected intraperitoneally. Animals being fed OVA or snOVA under acid-suppressive medication developed significantly elevated levels of IgE, and increased titers of specific IgG1 and IgG2a antibodies. Interestingly, oral immunizations of nOVA under anti-acid treatment did not result in IgG and IgE formation. In contrast, intraperitoneal immunization induced high levels of OVA specific IgE, which were significantly increased in the group that received nOVA by injection. Furthermore, nOVA triggered significantly enhanced mediator release from RBL cells passively sensitized with sera from allergic mice. Gastric digestion experiments demonstrated protein nitration to interfere with protein stability as nOVA was easily degraded, whereas OVA and snOVA remained stable up to 120 min. Additionally, HPLC-chip-MS/MS analysis showed that one tyrosine residue (Y(107)) being very efficiently nitrated is part of an ovalbumin epitope recognized exclusively after oral sensitization.These data indicated that despite the enhanced triggering capacity in existing allergy, nitration of OVA may be associated with a reduced de novo sensitizing capability via the oral route due to enhanced protein digestibility and/or changes in antibody epitopes

X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes

X-linked intellectual disability (XLID) is a clinically and genetically heterogeneous disorder. During the past two decades in excess of 100 X-chromosome ID genes have been identified. Yet, a large number of families mapping to the X-chromosome remained unresolved suggesting that more XLID genes or loci are yet to be identified. Here, we have investigated 405 unresolved families with XLID. We employed massively parallel sequencing of all X-chromosome exons in the index males. The majority of these males were previously tested negative for copy number variations and for mutations in a subset of known XLID genes by Sanger sequencing. In total, 745 X-chromosomal genes were screened. After stringent filtering, a total of 1297 non-recurrent exonic variants remained for prioritization. Co-segregation analysis of potential clinically relevant changes revealed that 80 families (20%) carried pathogenic variants in established XLID genes. In 19 families, we detected likely causative protein truncating and missense variants in 7 novel and validated XLID genes (CLCN4, CNKSR2, FRMPD4, KLHL15, LAS1L, RLIM and USP27X) and potentially deleterious variants in 2 novel candidate XLID genes (CDK16 and TAF1). We show that the CLCN4 and CNKSR2 variants impair protein functions as indicated by electrophysiological studies and altered differentiation of cultured primary neurons from Clcn4−/− mice or after mRNA knock-down. The newly identified and candidate XLID proteins belong to pathways and networks with established roles in cognitive function and intellectual disability in particular. We suggest that systematic sequencing of all X-chromosomal genes in a cohort of patients with genetic evidence for X-chromosome locus involvement may resolve up to 58% of Fragile X-negative cases

Exome-wide Rare Variant Analysis Identifies TUBA4A Mutations Associated with Familial ALS

Exome sequencing is an effective strategy for identifying human disease genes. However, this methodology is difficult in late-onset diseases where limited availability of DNA from informative family members prohibits comprehensive segregation analysis. To overcome this limitation, we performed an exome-wide rare variant burden analysis of 363 index cases with familial ALS (FALS). The results revealed an excess of patient variants within TUBA4A, the gene encoding the Tubulin, Alpha 4A protein. Analysis of a further 272 FALS cases and 5,510 internal controls confirmed the overrepresentation as statistically significant and replicable. Functional analyses revealed that TUBA4A mutants destabilize the microtubule network, diminishing its repolymerization capability. These results further emphasize the role of cytoskeletal defects in ALS and demonstrate the power of gene-based rare variant analyses in situations where causal genes cannot be identified through traditional segregation analysis

Ten millennia of hepatitis B virus evolution

Hepatitis B virus (HBV) has been infecting humans for millennia and remains a global health problem, but its past diversity and dispersal routes are largely unknown. We generated HBV genomic data from 137 Eurasians and Native Americans dated between similar to 10,500 and similar to 400 years ago. We date the most recent common ancestor of all HBV lineages to between similar to 20,000 and 12,000 years ago, with the virus present in European and South American hunter-gatherers during the early Holocene. After the European Neolithic transition, Mesolithic HBV strains were replaced by a lineage likely disseminated by early farmers that prevailed throughout western Eurasia for similar to 4000 years, declining around the end of the 2nd millennium BCE. The only remnant of this prehistoric HBV diversity is the rare genotype G, which appears to have reemerged during the HIV pandemic.Molecular Technology and Informatics for Personalised Medicine and Healt

Genotype-Specific Synthesis and Secretion of Spliced Hepatitis B Virus Genomes in Hepatoma Cells

AbstractHepatitis B virus-infected patients frequently have viral particles with DNA derived from differently spliced RNA. Which factors influence the synthesis of these splice variants is unclear. We analysed the type of splice variants produced from different genotypes and determined whether they are secreted as efficiently as wild-type virus. We demonstrate production of a single splice variant from genotypes D, C, and E as dominant species in two hepatoma cell lines. The type of minor splice variants synthesised varied between genotypes but was identical in both hepatoma cell lines. A novel splice variant with a deletion in the core gene was identified for genotype D. Viral DNA from intracellular compared with extracellular viral particles was spliced approximately five times more often than wild-type-sized genomes. A variable amount of the major splice variant was also identified in sera from patients infected with genotypes A, D, and C. These data indicate genotype A-, C-, D-, and E- as well as hepatoma cell line-independent synthesis of a dominant single splice variant and argue for a biological function of the corresponding splice sites. This study clearly demonstrates the intracellular accumulation of viral particles containing spliced genomes and offers a tool for the investigation of underlying mechanisms

coTRaCTE predicts co-occurring transcription factors within cell-type specific enhancers

Cell-type specific gene expression is regulated by the combinatorial action of transcription factors (TFs). In this study, we predict transcription factor (TF) combinations that cooperatively bind in a cell-type specific manner. We first divide DNase hypersensitive sites into cell-type specifically open vs. ubiquitously open sites in 64 cell types to describe possible cell-type specific enhancers. Based on the pattern contrast between these two groups of sequences we develop "co-occurring TF predictor on Cell-Type specific Enhancers" (coTRaCTE) - a novel statistical method to determine regulatory TF co-occurrences. Contrasting the co-binding of TF pairs between cell-type specific and ubiquitously open chromatin guarantees the high cell-type specificity of the predictions. coTRaCTE predicts more than 2000 co-occurring TF pairs in 64 cell types. The large majority (70%) of these TF pairs is highly cell-type specific and overlaps in TF pair co-occurrence are highly consistent among related cell types. Furthermore, independently validated co-occurring and directly interacting TFs are significantly enriched in our predictions. Focusing on the regulatory network derived from the predicted co-occurring TF pairs in embryonic stem cells (ESCs) we find that it consists of three subnetworks with distinct functions: maintenance of pluripotency governed by OCT4, SOX2 and NANOG, regulation of early development governed by KLF4, STAT3, ZIC3 and ZNF148 and general functions governed by MYC, TCF3 and YY1. In summary, coTRaCTE predicts highly cell-type specific co-occurring TFs which reveal new insights into transcriptional regulatory mechanisms