Multiple sclerosis is an immune-mediated demyelinating disease of unknown etiology that presents with either a chronic-progressive or relapsing-remitting clinical course. Theiler's murine ...encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) and relapsing-remitting experimental autoimmune encephalomyelitis (R-EAE) in the SJL/J mouse are both relevant murine CD4+ T cell-mediated demyelinating models that recapitulate the multiple sclerosis disease phenotypes. To determine the cellular and molecular basis for these observed differences in clinical course, we quantitatively analyzed the temporal expression of pro- and antiinflammatory cytokine mRNA expression in the central nervous system (CNS) and the phenotype of the inflammatory mononuclear infiltrates. TMEV-infected SJL/J mice expressed IFN-gamma, TNF-alpha, IL-10, and IL-4 mRNA during the preclinical phase, and their levels continued to increase throughout the duration of the chronic-progressive disease course. These data correlated with the continued presence of both CD4+ T cells and F4/80+ macrophages within the CNS infiltrates. In contrast, SJL/J mice with PLP(139-151)-induced R-EAE displayed a biphasic pattern of CNS expression for the proinflammatory cytokines, IFN-gamma and TNF-alpha, with expression peaking at the height of the acute phase and relapse(s). This pattern correlated with dynamic changes in the CD4+ T cell and F4/80+ macrophage populations during relapsing-remitting disease progression. Interestingly, IL-4 message was undetectable until disease remission(s), demonstrating its potential role in the intrinsic regulation of ongoing disease, whereas IL-10 was continuously expressed, arguing against a regulatory role in either disease. These data suggest that the kinetics of cytokine expression together with the nature of the persistent inflammatory infiltrates are major contributors to the differences in clinical course between TMEV-IDD and R-EAE.
Tenosynovial giant-cell tumor (TGCT) and pigmented villonodular synovitis (PVNS) are related conditions with features of both reactive inflammatory disorders and clonal neoplastic proliferations. ...Chromosomal translocations involving chromosome 1p13 have been reported in both TGCT and PVNS. We confirm that transiocations involving p1pl3 are present in a majority of cases of TGCT and PVNS and show that CSF1 is the gene at the chromosome lp13 breakpoint. In some cases of both TGCT and PVNS, CSF1 is fused to COL6A3 (2q35). The CSF1 translocations result in overexpression of CSF1. In cases of TGCT and PVNS carrying this translocation, it is present in a minority of the intratumoral cells, leading to CSF1 expression only in these cells, whereas the majority of cells express CSFIR but not CSF1, suggesting a tumor-landscaping effect with aberrant CSF1 expression in the neoplastic cells, leading to the abnormal accumulation of nonneoplastic cells that form a tumorous mass.
MINERvA neutrino detector response measured with test beam data Aliaga, L.; Altinok, O.; Araujo Del Castillo, C. ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
07/2015, Letnik:
789, Številka:
C
Journal Article
Recenzirano
Odprti dostop
The MINERvA collaboration operated a scaled-down replica of thesolid scintillator tracking and sampling calorimeter regions of the MINERvA detector in a hadron test beam at the Fermilab Test Beam ...Facility. This paper reports measurements with samples of protons, pions, and electrons from 0.35 to 2.0GeV/c momentum. The calorimetric response to protons, pions, and electrons is obtained from these data. A measurement of the parameter in Birks׳ law and an estimate of the tracking efficiency are extracted from the proton sample. Overall the data are well described by a Geant4-based Monte Carlo simulation of the detector and particle interactions with agreements better than 4% for the calorimetric response, though some features of the data are not precisely modeled. These measurements are used to tune the MINERvA detector simulation and evaluate systematic uncertainties in support of the MINERvA neutrino cross-section measurement program.
Heme is the most bioavailable form of dietary iron and a component of many cellular proteins. Controversy exists as to whether heme uptake occurs via specific transport mechanisms or passive ...diffusion. The aims of this study were to quantify cellular heme uptake with a fluorescent heme analog and to determine whether heme uptake is mediated by a heme transporter in intestinal and hepatic cell lines. A zinc-substituted porphyrin, zinc mesoporphyrin (ZnMP), was validated as a heme homolog in uptake studies of intestinal (Caco-2, I-407) and hepatic (HepG2) cell lines. Uptake experiments to determine time dependence, heme inhibition, concentration dependence, temperature dependence, and response to the heme synthesis inhibitor succinylacetone were performed. Fluorescence microscope images were used to quantify uptake and determine the cellular localization of ZnMP; ZnMP uptake was seen in intestinal and hepatic cell lines, with cytoplasmic uptake and nuclear sparing. Uptake was dose- and temperature dependent, inhibited by heme competition, and saturated over time. Preincubation with succinylacetone augmented uptake, with an increased initial uptake rate. These findings establish a new method for quantifying heme uptake in individual cells and provide strong evidence that this uptake is a regulated, carrier-mediated process.
We previously found that gene transduction by adeno-associated virus (AAV) vectors in cell culture can be stimulated over 100-fold by treatment of the target cells with agents that affect DNA ...metabolism, such as irradiation or topoisomerase inhibitors. Here we show that previous γ -irradiation increased the transduction rate in mouse liver by up to 900-fold, and the topoisomerase inhibitor etoposide increased transduction by about 20-fold. Similar rates of hepatic transduction were obtained by direct injection of the liver or by systemic delivery via tail vein injection. Hepatocytes were much more efficiently transduced than other cells after systemic delivery, and up to 3% of all hepatocytes could be transduced after one vector injection. The presence of wild-type AAV, which contaminates many AAV vector preparations, was required to observe a full response to γ -irradiation. Injection of mice with AAV vectors encoding human clotting factor IX after γ -irradiation resulted in synthesis of low levels of human clotting factor IX for the 5-month period of observation. These studies show the potential of targeted gene transduction of the liver by AAV vectors for treatment of various hematological or metabolic diseases.
The current trend in industry is to add small amounts of very fine or nano-particles to already existing products in hopes that the combination of particles will exhibit some enhanced behavior. A ...science is developing around the addition of these small particles and the appearance of certain chemical behaviors that they cause in the bulk. In addition, techniques are being developed that allow surface modification of many products. It has become a routine to coat particles with hydrophobic or hydrophilic coatings to achieve certain behaviors in solutions or gels. However, little attention is paid to the effect that these surface modifications and small particle interactions may have on the cohesive nature of the bulk particulate material. One intriguing question to be answered is: can methodologies or theories be postulated to predict the bulk cohesion of a given particle assembly after a prescribed surface modification or the addition of custom nano-particles? This paper examines the strength behavior of hydrophobic particles in moist or wet environments. In some instances the effect of liquid addition to hydrophobic surfaces dramatically reduces the bulk unconfined yield strength. This is likely due to the reduction in inter-particle friction from hydrodynamic effects. However, some particle sizes and degrees of hydrophobicity show an increase of cohesive behavior as moisture is added to the system. Finer particles tend to first exhibit a reduction in strength followed by an increase as the moisture content is increased. In any event, there is a non-linear relationship between particle size, liquid binder content, and the hydrophobic nature of the surface which is examined in this paper.
Display omitted Bulk unconfined strength of a powder or granular material depends on the adhesion forces and frictional forces between individual particles. In the case of hydrophobic surfaces strength often decreases with increasing water content. However the bulk yield strength is also a function of the structure of the particle matrix and can increase with increasing moisture content. The number of major contacts between particles in the matrix also plays a significant role in the unconfined yield strength. In fact, the cross sectional area occupied by major contacts and the inter-particle friction can be combined in such a way as to correlate with bulk strength values measured using standard test equipment.
The development of neutralizing antibodies, referred to as inhibitors, against factor VIII is a major complication associated with FVIII infusion therapy for the treatment of hemophilia A (HA). ...Previous studies have shown that a subset of HA patients and a low percentage of healthy individuals harbor non-neutralizing anti-FVIII antibodies that do not elicit the clinical manifestations associated with inhibitor development.
To assess HA patients' anti-FVIII antibody profiles as potential predictors of clinical outcomes.
A fluorescence immunoassay (FLI) was used to detect anti-FVIII antibodies in 491 samples from 371 HA patients.
Assessments of antibody profiles showed that the presence of anti-FVIII IgG1 , IgG2 or IgG4 correlated qualitatively and quantitatively with the presence of an FVIII inhibitor as determined with the Nijmegen-Bethesda assay (NBA). Forty-eight patients with a negative inhibitor history contributed serial samples to the study, including seven patients who had negative NBA titers initially and later converted to being NBA-positive. The FLI detected anti-FVIII IgG1 in five of those seven patients prior to their conversion to NBA-positive. Five of 15 serial-sample patients who had a negative inhibitor history and had anti-FVIII IgG1 later developed an inhibitor, as compared with two of 33 patients with a negative inhibitor history without anti-FVIII IgG1 .
These data provide a rationale for future studies designed both to monitor the dynamics of anti-FVIII antibody profiles in HA patients as a potential predictor of future inhibitor development and to assess the value of the anti-FVIII FLI as a supplement to traditional inhibitor testing.
West Nile virus is a pathogen of concern for both human and wildlife health, Although many aspects of the ecology of West Nile virus are well understood, the mechanisms by which this and similar ...mosquito-borne viruses overwinter and become reinitiated each spring in temperate regions is not known. A thorough understanding of this mechanism is crucial to risk assessment and development of control strategies. One of the hypotheses to explain the mechanism by which this virus persists from year to year is the spring recrudescence of latent virus in avian reservoir hosts. Stress-related immunosuppression is implicated in the recrudescence of latent viruses in birds. We tested the spring recrudescence hypothesis in a controlled laboratory experiment using hatching-year gray catbirds (Dumatella carolinensis) captured in northern Ohio (July–August 2006), Catbirds (n = 60) were experimentally infected (September 2006) and later examined for the effects of immuno-suppression through exogenous hormones and artificially induced migratory disposition, We found no effect of either testosterone or migratory behavior on infection status in any of the treatment birds. Moreover, we detected no viral RNA in the kidney, spleen, brain, or liver upon necropsy at 24 wk postinfection.
PDF
