Modeling inflammation and oxidative stress in gastrointestinal disease development using novel organotypic culture systems

Gastroesophageal reflux disease (GERD), Barrett's esophagus (BE), graft-versus-host disease (GVHD), and inflammatory bowel diseases such as ulcerative colitis and Crohn's disease are common human gastrointestinal diseases that share inflammation as a key driver for their development. A general outcome resulting from these chronic inflammatory conditions is increased oxidative stress. Oxidative stress is caused by the generation of reactive oxygen and nitrogen species that are part of the normal inflammatory response, but are also capable of damaging cellular DNA, protein, and organelles. Damage to DNA can include DNA strand breaks, point mutations due to DNA adducts, as well as alterations in methylation patterns leading to activation of oncogenes or inactivation of tumor suppressors. There are a number of significant long-term consequences associated with chronic oxidative stress, most notably cancer. Infiltrating immune cells and stromal components of tissue including fibroblasts contribute to dynamic changes occurring in tissue related to disease development. Immune cells can potentiate oxidative stress, and fibroblasts have the capacity to contribute to advanced growth and proliferation of the epithelium and any resultant cancers. Disease models for GERD, BE, GVHD, and ulcerative colitis based on three-dimensional human cell and tissue culture systems that recapitulate in vivo growth and differentiation in inflammatory-associated microphysiological environments would enhance our understanding of disease progression and improve our ability to test for disease-prevention strategies. The development of physiologically relevant, human cell-based culture systems is therefore a major focus of our research. These novel models will be of enormous value, allowing us to test hypotheses and advance our understanding of these disorders, and will have a translational impact allowing us to more rapidly develop therapeutic and chemopreventive agents. In summary, this work to develop advanced human cell-based models of inflammatory conditions will greatly improve our ability to study, prevent, and treat GERD, BE, GVHD, and inflammatory bowel disease. The work will also foster the development of novel therapeutic and preventive strategies that will improve patient care for these important clinical conditions. © 2013 BioMed Central Ltd

A model of Bˉ0→D∗+ωπ−\bar{B}^0\to D^{*+}\omega\pi^- decay

We suggest a parameterization of the matrix element for $\bar{B}^0\to D^{*+}\omega\pi^-$ decay using kinematic variables convenient for experimental analysis. The contributions of intermediate $\omega\pi$- and $D^{**}$-states up to spin 3 have been taken into account. The angular distributions for each discussed hypothesis have been obtained and analysed using Monte-Carlo simulation.Comment: 24 pages, 9 figures, 1 table; V2: text in some places improved and acknowledgments adde

Second order QCD corrections to inclusive semileptonic b \to Xc l \bar \nu_l decays with massless and massive lepton

We extend previous computations of the second order QCD corrections to semileptonic b \to c inclusive transitions, to the case where the charged lepton in the final state is massive. This allows accurate description of b \to c \tau \bar \nu_\tau decays. We review techniques used in the computation of O(\alpha_s^2) corrections to inclusive semileptonic b \to c transitions and present extensive numerical studies of O(\alpha_s^2) QCD corrections to b \to c l \bar \nu_l decays, for l =e, \tau.Comment: 30 pages, 4 figures, 5 table

What happens if you single out? An experiment

We present an experiment investigating the effects of singling out an individual on trust and trustworthiness. We find that (a) trustworthiness falls if there is a singled out subject; (b) non-singled out subjects discriminate against the singled out subject when they are not responsible of the distinct status of this person; (c) under a negative frame, the singled out subject returns significantly less; (d) under a positive frame, the singled out subject behaves bimodally, either selecting very low or very high return rates. Overall, singling out induces a negligible effect on trust but is potentially disruptive for trustworthiness

Germ Line Origin and Somatic Mutations Determine the Target Tissues in Systemic AL-Amyloidosis

BACKGROUND: Amyloid is insoluble aggregated proteins deposited in the extra cellular space. About 25 different proteins are known to form amyloid in vivo and are associated with severe diseases such as Alzheimer's disease, prion diseases and type-2 diabetes. Light chain (AL) -amyloidosis is unique among amyloid diseases in that the fibril protein, a monoclonal immunoglobulin light chain, varies between individuals and that no two AL-proteins with identical primary structures have been described to date. The variability in tissue distribution of amyloid deposits is considerably larger in systemic AL-amyloidosis than in any other form of amyloidosis. The reason for this variation is believed to be based on the differences in properties of the amyloidogenic immunoglobulin light chain. However, there is presently no known relationship between the structure of an AL-protein and tissue distribution. METHODOLOGY/PRINCIPAL FINDINGS: We compared the pattern of amyloid deposition in four individuals with amyloid protein derived from variable light chain gene O18-O8, the source of a high proportion of amyloidogenic light chains, and in whom all or most of the fibril protein had been determined by amino acid sequencing. In spite of great similarities between the structures of the proteins, there was a pronounced variability in deposition pattern. We also compared the tissue distribution in these four individuals with that of four other patients with AL-amyloid derived from the L2-L16 gene. Although the interindividual variations were pronounced, liver and kidney involvement was much more evident in the latter four. CONCLUSIONS/SIGNIFICANCE: We conclude that although the use of a specific gene influences the tissue distribution of amyloid, each light chain exhibits one or more determinants of organ-specificity, which originate from somatic mutations and post-translational modifications. Eventual identification of such determinants could lead to improved treatment of patients with AL amyloidosis

Unresolved orthology and peculiar coding sequence properties of lamprey genes: the KCNA gene family as test case

Background:In understanding the evolutionary process of vertebrates, cyclostomes (hagfishes and lamprey) occupy crucial positions. Resolving molecular phylogenetic relationships of cyclostome genes with gnathostomes (jawed vertebrates) genes is indispensable in deciphering both the species tree and gene trees. However, molecular phylogenetic analyses, especially those including lamprey genes, have produced highly discordant results between gene families. To efficiently scrutinize this problem using partial genome assemblies of early vertebrates, we focused on the potassium voltage-gated channel, shaker-related (KCNA) family, whose members are mostly single-exon.Results:Seven sea lamprey KCNA genes as well as six elephant shark genes were identified, and their orthologies to bony vertebrate subgroups were assessed. In contrast to robustly supported orthology of the elephant shark genes to gnathostome subgroups, clear orthology of any sea lamprey gene could not be established. Notably, sea lamprey KCNA sequences displayed unique codon usage pattern and amino acid composition, probably associated with exceptionally high GC-content in their coding regions. This lamprey-specific property of coding sequences was also observed generally for genes outside this gene family.Conclusions:Our results suggest that secondary modifications of sequence properties unique to the lamprey lineage may be one of the factors preventing robust orthology assessments of lamprey genes, which deserves further genome-wide validation. The lamprey lineage-specific alteration of protein-coding sequence properties needs to be taken into consideration in tackling the key questions about early vertebrate evolution

Using motivational techniques to reduce cardiometabolic risk factors in long term psychiatric inpatients: A naturalistic interventional study

Background People with severe mental illness have markedly reduced life expectancy; cardiometabolic disease is a major cause. Psychiatric hospital inpatients have elevated levels of cardiometabolic risk factors and are to a high degree dependent of the routines and facilities of the institutions. Studies of lifestyle interventions to reduce cardiometabolic risk in psychiatric inpatients are few. The current study aimed at assessing the feasibility and effects of a lifestyle intervention including Motivational Interviewing (MI) on physical activity levels, cardiometabolic risk status and mental health status in psychotic disorder inpatients. Methods Prospective naturalistic intervention study of 83 patients at long term inpatient psychosis treatment wards in South-Eastern Norway. Patients were assessed 3–6 months prior to, at start and 6 months after a life-style intervention program including training of staff in MI, simple changes in routines and improvements of facilities for physical exercise. Assessments were done by clinical staff and included level of physical activity, motivation, life satisfaction, symptom levels (MADRS, AES-C, PANSS, and GAF) as well as anthropometric and biochemical markers of cardiometabolic risk. A mixed model was applied to analyze change over time. Results A total of 88% of patients received MI interventions, with a mean of 2.5 MI interventions per week per patient. The physical activity level was not increased, but activity level was positively associated with motivation and negatively associated with positive symptoms. Triglyceride levels and number of smokers were significantly reduced and a significant decrease in symptom levels was observed. Conclusions The current results suggest that a simple, low cost life-style intervention program focusing on motivational change is feasible and may reduce symptoms and improve lifestyle habits in psychosis patients in long term treatment facilities. Similar programs may easily be implemented in other psychiatric hospitals.submittedVersio

Factorization at Subleading Power and Irreducible Uncertainties in Bˉ→Xsγ\bar B\to X_s\gamma Decay

Using methods from soft-collinear and heavy-quark effective theory, a systematic factorization analysis is performed for the $\bar B\to X_s\gamma$ photon spectrum in the endpoint region $m_b-2E_\gamma={\cal O}(\Lambda_{\rm QCD})$. It is proposed that, to all orders in $1/m_b$, the spectrum obeys a novel factorization formula, which besides terms with the structure $H\,J\otimes S$ familiar from inclusive $\bar B\to X_u l\,\bar\nu$ decay distributions contains "resolved photon" contributions of the form $H\,J\otimes S\otimes\bar J$ and $H\,J\otimes S\otimes\bar J\otimes\bar J$. Here $S$ and $\bar J$ are new soft and jet functions, whose form is derived. These contributions arise whenever the photon couples to light partons instead of coupling directly to the effective weak interaction. The new contributions appear first at order $1/m_b$ and are related to operators other than $Q_{7\gamma}$ in the effective weak Hamiltonian. They give rise to non-vanishing $1/m_b$ corrections to the total decay rate, which cannot be described using a local operator product expansion. A systematic analysis of these effects is performed at tree level in hard and hard-collinear interactions. The resulting uncertainty on the decay rate defined with a cut $E_\gamma>1.6$ GeV is estimated to be approximately $\pm 5$. It could be reduced by an improved measurement of the isospin asymmetry $\Delta_{0-}$ to the level of $\pm 4$. We see no possibility to reduce this uncertainty further using reliable theoretical methods.Comment: 63 pages, 11 Figures, Journal Versio