A major challenge to understanding the response of materials to extreme environments (e.g., nuclear fuels/waste forms and fusion materials) is to unravel the processes by which a material can ...incorporate atomic-scale disorder, and at the same time, remain crystalline. While it has long been known that all condensed matter, even liquids and glasses, possess short-range order, the relation between fully-ordered, disordered, and aperiodic structures over multiple length scales is not well understood. For example, when defects are introduced (via pressure or irradiation) into materials adopting the pyrochlore structure, these complex oxides either disorder over specific crystallographic sites, remaining crystalline, or become aperiodic. Here we present neutron total scattering results characterizing the irradiation response of two pyrochlores, one that is known to disorder (Er2Sn2O7) and the other to amorphize (Dy2Sn2O7) under ion irradiation. The results demonstrate that in both cases, the local pyrochlore structure is transformed into similar short range configurations that are best fit by the orthorhombic weberite structure, even though the two compositions have distinctly different structures, aperiodic vs. disordered-crystalline, at longer length scales. Thus, a material's resistance to amorphization may not depend primarily on local defect formation energies, but rather on the structure's compatibility with meso-scale modulations of the local order in a way that maintains long-range periodicity.
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A major challenge to understanding the response of materials to extreme environments (e.g., nuclear fuels/waste forms and fusion materials) is to unravel the processes by which a material can ...incorporate atomic-scale disorder, and at the same time, remain crystalline. While it has long been known that all condensed matter, even liquids and glasses, possess short-range order, the relation between fully-ordered, disordered, and aperiodic structures over multiple length scales is not well understood. For example, when defects are introduced (via pressure or irradiation) into materials adopting the pyrochlore structure, these complex oxides either disorder over specific crystallographic sites, remaining crystalline, or become aperiodic. Here we present neutron total scattering results characterizing the irradiation response of two pyrochlores, one that is known to disorder (Er2Sn2O7) and the other to amorphize (Dy2Sn2O7) under ion irradiation. The results demonstrate that in both cases, the local pyrochlore structure is transformed into similar short range configurations that are best fit by the orthorhombic weberite structure, even though the two compositions have distinctly different structures, aperiodic vs. disordered-crystalline, at longer length scales. Thus, a material's resistance to amorphization may not depend primarily on local defect formation energies, but rather on the structure's compatibility with meso-scale modulations of the local order in a way that maintains long-range periodicity.
In Devine Bros., Inc. v. Commissioner (2003), the Tax Court held that salary and bonuses paid to a major shareholder and officer of the corporation were not unreasonable compensation under section ...162(a)(l) of the Code. In arriving at that result, the court, in effect, blended two tests to determine what is considered reasonalbe compensation paid to employees of corporations. Part I of this Note summarizes the facts of Devine Bros. and discusses the relevant authorities and case law. Part II presents the parties' arguments and explores the opinion of the court, explaining the court's reasoning behind its result. Part III analyzes the reasoning used by the court to support the taxpayer's arguments and highlights holes in those arguments that the Service could have exploited to rebut the presumption created by the taxpayer's evidence. Part III further explains how the vagueness of the opinion is fully attributable to the court because the law with respect to section 162(a)(l) is not entirely clear.
Genome-wide association studies (GWAS) in several populations have demonstrated significant association of the IL23R gene with IBD (Crohn's disease (CD) and ulcerative colitis (UC)) and psoriasis, ...suggesting that perturbation of the IL-23 signaling pathway is relevant to the pathophysiology of these diseases. One particular variant, R381Q (rs11209026), confers strong protection against development of CD. We investigated the effects of this variant in primary T cells from healthy donors carrying IL23R(R381) and IL23R(Q381) haplotypes. Using a proprietary anti-IL23R antibody, ELISA, flow cytometry, phosphoflow and real-time RT-PCR methods, we examined IL23R expression and STAT3 phosphorylation and activation in response to IL-23. IL23R(Q381) was associated with reduced STAT3 phosphorylation upon stimulation with IL-23 and decreased number of IL-23 responsive T-cells. We also observed slightly reduced levels of proinflammatory cytokine secretion in IL23R(Q381) positive donors. Our study shows conclusively that IL23R(Q381) is a loss-of-function allele, further strengthening the implication from GWAS results that the IL-23 pathway is pathogenic in human disease. This data provides an explanation for the protective role of R381Q in CD and may lead to the development of improved therapeutics for autoimmune disorders like CD.
Systemic lupus erythematosus (SLE) is a serious systemic autoimmune disorder that affects multiple organ systems and is characterized by unpredictable flares of disease. Recent evidence indicates a ...role for type I interferon (IFN) in SLE pathogenesis; however, the downstream effects of IFN pathway activation are not well understood. Here we test the hypothesis that type I IFN-regulated proteins are present in the serum of SLE patients and correlate with disease activity.
We performed a comprehensive survey of the serologic proteome in human SLE and identified dysregulated levels of 30 cytokines, chemokines, growth factors, and soluble receptors. Particularly striking was the highly coordinated up-regulation of 12 inflammatory and/or homeostatic chemokines, molecules that direct the movement of leukocytes in the body. Most of the identified chemokines were inducible by type I IFN, and their levels correlated strongly with clinical and laboratory measures of disease activity.
These data suggest that severely disrupted chemokine gradients may contribute to the systemic autoimmunity observed in human SLE. Furthermore, the levels of serum chemokines may serve as convenient biomarkers for disease activity in lupus.
The mechanisms responsible for the immunosuppression associated with sepsis or some chronic blood infections remain poorly understood. Here we show that infection with a malaria parasite (Plasmodium ...berghei) or simple systemic exposure to bacterial or viral Toll-like receptor ligands inhibited cross-priming. Reduced cross-priming was a consequence of downregulation of cross-presentation by activated dendritic cells due to systemic activation that did not otherwise globally inhibit T cell proliferation. Although activated dendritic cells retained their capacity to present viral antigens via the endogenous major histocompatibility complex class I processing pathway, antiviral responses were greatly impaired in mice exposed to Toll-like receptor ligands. This is consistent with a key function for cross-presentation in antiviral immunity and helps explain the immunosuppressive effects of systemic infection. Moreover, inhibition of cross-presentation was overcome by injection of dendritic cells bearing antigen, which provides a new strategy for generating immunity during immunosuppressive blood infections.
CXCL12/CXCR4 signaling is critical for cortical interneuron migration and their final laminar distribution. No information is yet available on CXCR7, a newly defined CXCL12 receptor. Here we ...demonstrated that CXCR7 regulated interneuron migration autonomously, as well as nonautonomously through its expression in immature projection neurons. Migrating cortical interneurons coexpressed
Cxcr4 and
Cxcr7, and
Cxcr7
–/–
and
Cxcr4
–/–
mutants had similar defects in interneuron positioning. Ectopic CXCL12 expression and pharmacological blockade of CXCR4 in
Cxcr7
–/–
mutants showed that both receptors were essential for responding to CXCL12 during interneuron migration. Furthermore, live imaging revealed that
Cxcr4
–/–
and
Cxcr7
–/–
mutants had opposite defects in interneuron motility and leading process morphology. In vivo inhibition of Gα(i/o) signaling in migrating interneurons phenocopied the interneuron lamination defects of
Cxcr4
–/–
mutants. On the other hand, CXCL12 stimulation of CXCR7, but not CXCR4, promoted MAP kinase signaling. Thus, we suggest that CXCR4 and CXCR7 have distinct roles and signal transduction in regulating interneuron movement and laminar positioning.
► Migrating immature cortical interneurons coexpress Cxcr4 and Cxcr7 ► Cxcr4
–/–
and Cxcr7
–/–
mutants have opposite defects in interneuron motility ► CXCR4 and CXCR7 are both essential for responding to CXCL12 ► CXCR4 and CXCR7 signal through different pathways in the developing interneurons
Abstract
Objectives
This research examined main and moderating effects of global depressive symptoms upon in-the-moment associations of pain and affect among individuals with knee osteoarthritis ...(OA). Effects of depression on short-term change in pain and affect were also examined.
Method
Older adults with physician-confirmed OA (N = 325) completed a baseline interview tapping global depressive symptoms, followed by an experience sampling protocol that captured momentary pain and affect 4 times daily for 7 days. Multilevel models controlling demographics and health conditions examined main and moderating effects of depression on momentary associations of pain with positive affect (PA) and negative affect (NA). Similar methods addressed short-term change in pain and affect. Auxiliary analyses explored broad associations of depressive symptoms with person-level averages and variability in pain and affect.
Results
Global depression predicted current pain, PA, and NA, as well as change in pain and affect over a 3- to 8-h period. Furthermore, both in the moment and over short periods, the association of pain and NA was stronger among persons higher in depressive symptoms. No moderating effect for the PA–pain association was found. Depressive symptoms were also associated with variability in pain and affect, particularly NA.
Discussion
Results confirm previous work on the relation of chronic pain with both global depressive symptoms and short-term affect. This research further demonstrates a unique moderating role of depression on the association of momentary pain with NA and suggests that the causal path may be stronger from pain to affect than vice versa.
G‐protein‐coupled receptors (GPCRs) are key mediators in cardiovascular physiology, yet frontline therapies for heart disease target only a small fraction of the cardiac GPCR repertoire. Moreover, ...there is emerging evidence that GPCRs implicated in taste (Tas1r and Tas2rs) have specific functions beyond the oral cavity. Our recent description of these receptors in heart tissue foreshadows a potential novel role in cardiac cells. In this study, we identified novel agonist ligands for cardiac‐Tas2rs to enable the functional investigation of these receptors in heart tissue. Five Tas2rs cloned from heart tissue were screened against a panel of 102 natural or synthetic bitter compounds in a heterologous expression system. We identified agonists for Tas2r108, Tas2r137, and Tas2r143 that were then tested in Langendorff‐perfused mouse hearts (from 8‐wk‐old male C57BL/6 mice). All Tas2r agonists tested exhibited concentration‐dependent effects, with agonists for Tas2r108 and Tas2r137, leading to a ~40% decrease in left ventricular developed pressure and an increase in aortic pressure, respectively. These responses were abrogated in the presence of Gα1 and Gβγ inhibitors (pertussis toxin and gallein). This study represents the first demonstration of profound Tas2r agonist‐induced, G protein‐dependent effects on mouse heart function.—Foster, S. R., Blank, K., See Hoe, L. E., Behrens, M., Meyerhof, W., Peart, J. N., Thomas, W. G., Bitter taste receptor agonists elicit G‐protein‐dependent negative inotropy in the murine heart. FASEB J. 28, 4497–4508 (2014). www.fasebj.org
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